ESTIV organizes free webinars on a monthly basis together with the American Society for Cellular and Computational Toxicology (ASCCT). These webinars cover a broad spectrum of topics relevant to the fields of in vitro and in silico toxicology. ESTIV members are welcome to propose topics and speakers at any time. All webinars are recorded, archived and available for ESTIV members.
Webinars – 2021
ESTIV and ASCCT Webinars are available for all to attend and watch at no cost.
July 21, 2021 – Bridging toxicology and research: COVID-19 initiatives
Wednesday, 21 July, 2021
10:00 – 11:30 EDT
Marco Travaglio, PhD student, MRC Toxicology Unit, School of Biological Sciences, University of Cambridge
Maria João Amorim, PhD, Instituto Gulbenkian de Ciência
Links between air pollution and COVID-19 in England
Presented by: Marco Travaglio
In the UK, the coronavirus disease 19 (COVID-19) has caused over 120,000 deaths. However, uncertainty remains surrounding environmental risk factors for this disease. In our study, we show a clear link between air pollution and COVID-19 in England. We compared SARS-CoV-2 cases and deaths recorded in public databases to both regional and subregional air pollution data monitored at multiple sites across England. Our results show that the levels of multiple markers of poor air quality, including nitrogen oxides PM2.5, are associated with increased COVID-19 deaths in England, after adjusting for population density and other socio-economic factors. We expanded our analysis using individual-level data from the UK Biobank and showed that particulate matters contribute to increased infectivity. Our results link the levels of some air pollutants to COVID-19 cases and adverse outcomes. This study provides a useful framework to guide health policies in countries affected by this pandemic. This was the first study to combine a population- and individual-level approach to investigate the impact of air pollution on COVID-19 infectivity and mortality in England. Our research uniquely places the disease within the context of potentially modifiable risk factors, providing a useful framework for implementing air quality management programmes for disease prevention and control.
COVID-19 through Adverse Outcome Pathways (AOP): building networks to understand the disease
Presented by: Maria João Amorim
The coronavirus disease 2019 (COVID-19) is an ongoing global public health problem caused by the severe acute respiratory syndrome coronavirus–2 (SARS-CoV-2) pandemics. Scientists around the world are producing invaluable data at an unprecedent speed in a mobilized effort to provide answers about this emerging virus. This webinar explains how the CIAO project is modelling COVID-19 pathogenesis at several layers by exploiting the Adverse Outcome Pathway (AOP) framework (www.ciao-covid.net). CIAO relies on an interdisciplinary crowdsourcing effort, synergizing experts of many fields to translate complex biology into simplified knowledge. It uses the open access Wiki platform to build evidence about the biological mode of action of the virus with the goal of informing policy and healthcare decisions. The project counts with the action of more than 65 scientists from 40 organizations around the world, which is steered by the European Commission, the Physicians Committee for Responsible Medicine and the Humane Society International.
June 23, 2021 – Human Induced Pluropotent Stem Cells (hIPSC) in Toxicology
Tuesday, June 23, 2021
10:00 – 11:30 EST / 16:00 – 17:30 CET
Recorded file: https://www.ascctox.org/webinar/80
Register here: https://zoom.us/webinar/register/WN_FqXntfoBRKimUYeGCbhkGA
Catherine Verfaillie, Leuven University
Anne Marie Vinggard, National Food Institute, Technical University of Denmark
“Multicellular 3D liver models based on hiPSC-derived liver cells“
Presented by Catherine Verfaillie
To address how toxic insults affect hepatocytes as well as non-parenchymal cells, murine or rat models are often used. However, interspecies differences between humans and rodents do not always allow extrapolating findings in animal models to the human patient. Therefore, human hepatoma cell lines with or without stellate cell, monocyte, and/or endothelial cell lines can be used. In addition, and more relevant, primary human liver cells can be used. However, It has long been established that when cultured on stiff culture plates, primary human hepatocytes (PHHs) very quickly lose functionality. This is also the case for hepatic stellate cells (HSCs) that become quickly activated, and liver sinusoidal endothelial cells (LSECs) that very quickly lose their typical sinusoidal endothelial characteristics. Especially for hepatocytes, numerous studies have demonstrated that this can at least in part be prevented when cells are cultured for instance in sandwich cultures, in spheroids or embedded in scaffolds. Although the latter best mimic human liver, the scarcity of human liver cells and high inter-donor variation represent important drawbacks. With the advent of pluripotent stem cells (PSCs), it is now possible to create PSC-derived hepatocyte-, HSC-, EC- and macrophage (Mφ)-like cells. As PSCs are an inexhaustible cell population, this approach overcomes the issues related to low cell numbers and inter-donor variability of primary samples. To create more complete liver models, co-cultures of PSC-hepatocyte-like cell (HLC) progeny with mesenchymal cells and human umbilical vein endothelial cells (HUVECs) have been created, and more recent studies created liver models by co-differentiation of PSCs to hepatocyte- and NPC-like cells directly in spheroids. An alternative is the assembly of pre-differentiated PSC-HLCs and -NPC-like cells into co-cultures. During this presentation, data will be presented from studies exploiting the latter concept to create in vitro liver models that are stable for several weeks, and can be used to test drug metabolisation, drug toxicity or induction of liver inflammation and fibrosis.
“Novel human pluripotent stem cell-based assays to predict developmental toxicity“
Presented by Anne Marie Vinggard
As women are exposed to a plethora of chemicals during pregnancy, it is important to evaluate their safety for the developing embryo. For this, human based models are needed for enabling reliable and large scale risk assessment1. Human induced pluripotent stem cells (hiPSC) are an excellent tool to model embryonic development as they can form embryoid bodies (EBs) that mirror the early embryo in many structural and functional aspects, and can undergo differentiation programs that reflect molecular mechanisms during embryonic development2. Here, we present our recently developed assays for predicting developmental toxicity using hiPSC.
We used three different hiPSC lines and differentiated the cells through EBs into cardiomyocytes. The cells were exposed to chemicals for the last six days of differentiation and the beating EBs analyzed on the last day4. In order to characterize our system and to study potential molecular mechanisms-of-action, we also investigated global and targeted gene expression levels and protein cardiac markers. We were able to show that our system mimics the first three weeks of embryonic development by analyzing markers for respective developmental stages3. Furthermore, the assay was able to detect the strong developmental toxicant thalidomide as positive while the neurodevelopmental toxicant valproic acid was negative. Interestingly, we also identified the fungicide epoxiconazole as a potentially hazardous chemical4 and studied the underlying mechanism-of-action. Moreover, we have created a human NKX2.5 reporter stem cell line for developmental toxicity testing with a greater sensitivity and a higher throughput5. In conclusion, we have developed two assays based on hiPSC that can predict developmental toxicity and that reflect key aspects of early embryonic development.
May 18, 2021 – New Approach Methods in genotoxicity and mechanistic toxicity testing for the animal-free safety assessment of novel pharmaceuticals and chemicals
Tuesday, May 18, 2021
10:00 – 11:00 EST / 16:00 – 17:00 CET
Register here: https://zoom.us/webinar/register/WN_FqXntfoBRKimUYeGCbhkGA
Presented by: Giel Hendriks, CEO, Toxys
Every year, large numbers of new compounds are being developed for a wide range of purposes. Due to the large numbers of compounds that require safety assessment, there is an increasing demand for rapid and reliable in vitro assays that assess their toxicity in an early phase of drug or product development. At the same time, there is a strong demand to reduce animal testing. We have therefore developed various in vitro cell-based assays for chemical safety assessment with the focus on understanding the mode-of-action (MoA) of toxic compounds.
ToxTracker is a unique stem cell-based reporter assay for reliable genotoxicity and carcinogenicity hazard identification. The ToxTracker assay reliably identifies genotoxic compounds and provides insight into their mode-of-action. The assay is able to discriminate between direct DNA reactivity and indirect genotoxicity related to oxidative stress or protein damage and can differentiate between genotoxic compounds with a clastogenic or aneugenic MoA. Various extensions of ToxTracker to further investigate the MoA of genotoxic compounds are combined in the ToxTracker suite.
ToxProfiler is a human cell reporter assay that can accurately quantify the cellular stress responses that are induced by chemicals. The unique combination of seven fluorescent reporter cell lines for oxidative stress, genetic stress, ER stress, autophagy, ion stress, protein stress and inflammation and automated live-cell confocal microscopy are applied to generate a toxicological fingerprint and provide insight into the toxic MoA of compounds.
These unique animal-free in vitro assays provide reliable and accurate toxicity information that is relevant to human health. The assays are used for early compound screening, follow-up testing and MoA assessment, potency ranking and chemical read-across and are particularly useful in weight-of-evidence (WoE) and adverse outcome pathway (AOP) approaches for chemical safety assessment.
April 21, 2021 – Legal and Policy Considerations for the Use of New Approach Methodologies (NAMs) in Chemical Risk Assessment
April 21, 2021
10:00 – 11:00 EST / 16:00 – 17:00 CET
View the presentations here :https://www.ascctox.org/webinar/76
Gary Marchant, PhD, JD, Sandra Day O’Connor College of Law, Arizona State U.
Kirk T. Hartley, JD, ToxicoGenomica and LSP Group LLC
February 25, 2021 – Quantitative in vitro to in vivo extrapolation (QIVIVE)
Thursday, February 25th, 2021
10:00AM – 11:30AM EST
- Martin Scholze, Centre for Pollution Research and Policy, Brunel University London, UK
- Ans Punt, Wageningen Food Safety Research, The Netherlands
Register here: https://zoom.us/webinar/register/WN_wsfqCX7uQciWxA1Lu0xc_A
Martin Scholze, Centre for Pollution Research and Policy, Brunel University London, UK
Quantitative in Vitro to in Vivo Extrapolation (QIVIVE) for Predicting Reduced Anogenital Distance produced by Anti-Androgenic Pesticides in a Rodent Model for Male Reproductive Disorders
Many pesticides can antagonize the androgen receptor(AR) or inhibit androgen synthesis in vitro but their potential to cause reproductive toxicity related to disruption of androgen action during fetal life is difficult to predict. Currently, no approaches for using in vitro data to anticipate such in vivo effects exist, and prioritization schemes that limit unnecessary animal testing are urgently needed. Here I will present a quantitative in vitro to in vivo extrapolation (QIVIVE) approach for predicting in vivo anti-androgenicity arising from gestational exposures and manifesting as a shortened anogenital distance (AGD) in male rats. It is built on a physiologically based pharmacokinetic (PBK) model to simulate concentrations of chemicals in the fetus resulting from maternal dosing. The QIVIVE approach was evaluated by using several well-studied model compounds and then applied to various current-use pesticides, all with in vitro evidence for anti-androgenicity but missing in vivo data. Here the QIVIVE model newly identified fludioxonil, cyprodinil, and dimethomorph as in vivo anti-androgens. With the examples investigated, this approach shows great promise for predicting in vivo anti-androgenicity (i.e., AGD shortening) for chemicals with in vitro activity and for minimizing unnecessary animal testing.
Ans Punt, Wageningen Food Safety Research, The Netherlands
A web-based toolbox to support quantitative in vitro-to-in vivo extrapolations (QIVIVE)
An important aspect within next generation non-animal toxicity testing strategies is the extrapolation of in vitro effect concentrations into (human) dose−response or potency information, also called quantitative in vitro-to-in vivo extrapolation (QIVIVE). Insights in dose-dependent plasma and tissue concentrations of a chemical are required to infer the dose levels that would be needed to reach the in vitro effective concentrations in the body. Physiologically based kinetic (PBK) modelling plays a crucial role in generating such insights. To support PBK-model development we have developed a web-based toolbox (www.qivivetools.wur.nl) that contains generic physiologically based-kinetic (PBK) models for rats and humans, including underlying calculation tools to predict plasma protein binding and tissue:plasma distribution. The PBK models within the toolbox allow to make first estimations of internal plasma and tissue concentrations of chemicals, based on the LogP and pKa of the chemical and values for intrinsic hepatic clearance and intestinal uptake. As case study, the toolbox was used to predict oral equivalent doses of in vitro ToxCast bioactivity data for the food additives methylparaben, propyl gallate, octyl gallate and dodecyl gallate. These oral equivalent doses were subsequently compared with human exposure estimates. The goal of the presentation is to provide a background on PBK model development and QIVIVE, making interactively use of the web-based toolbox.
January 14th, 2020 – ASCCT Award Winners Webinar: January 2021
Thursday, January 14 2021 10:00-11:15 AM US ET// 4:00 PM – 5:15 PM CET
Register here: https://zoom.us/webinar/register/WN_wsfqCX7uQciWxA1Lu0xc_A
The Ed Carney Predictive Toxicology Award recognizes the first author of an outstanding poster or platform presentation that will advance predictive toxicology, and is named after Dr. Ed Carney, a member and supporter of the ASCCT and a leader in the predictive toxicology field. The 2020 winner was Eva C.M. Vitucci from University of North Carolina, Chapel Hill to for her presentation “Identifying the Molecular Mechanisms of Air Pollution-Induced Cardiovascular Disease”.
The Ray Tice Tox21 Student Award is presented to recognize the best student presentation during the meeting and was established with a generous donation from Dr. Ray Tice, a leader in implementing and setting the stage for Toxicity Testing in the 21st Century. The 2020 winner was Ms. Sherri Bloch from Université de Montréal for her presentation “Using in Vitro Data to Derive Acceptable Exposure Levels: A Case Study on PBDE Developmental Neurotoxicity”.
Using in vitro data to derive acceptable exposure levels: Case studies on PBDE
developmental neurotoxicity and DDE obesogenicity
Presented by: Sherri Bloch
Current acceptable exposure levels are mostly based on animal models, which are costly,
time-consuming, and may poorly predict adverse outcomes in humans. There is a need for
alternative testing methods that are faster, cheaper, and provide human-relevant information.
We aimed to evaluate a method using human in vitro data and biological modeling to calculate acceptable exposure levels through two case studies: One on PBDE developmental neurotoxicity and the other on p,p’-DDE obesogenicity due to early life exposure.
To accomplish our objectives, in vitro studies using human cells were compiled to select points of departure (POD) in the form of nominal medium concentrations. These were translated into cellular levels (target organ POD), and then converted into acceptable daily intakes and plasma concentrations in pregnant women using pharmacokinetic models of gestation/lactation and applying uncertainty factors. The final step of our methodology was the comparison of the derived chemical levels in maternal plasma to levels measured in epidemiological studies reporting associations between prenatal exposure and the adverse endpoints in children.
Estimated acceptable exposure levels and matching plasma levels showed concurrence with those measured in epidemiological studies, implying this approach may be viable. However, uncertainty factors need further investigation prior to application in risk assessment.
Identifying the Molecular Mechanisms of Air Pollution – Induced Cardiovascular Disease
Presented by: Eva Vitucci
An estimated 3.5-million people die annually from air pollution-induced cardiovascular disease (API-CVD). API-thrombosis (API-T) is a main contributor of these mortalities; however, the molecular mechanisms driving API-T are unclear. To identify these mechanisms we developed an in vitro model that represents the interface of the respiratory and cardiovascular system, the alveolar capillary region (ACR). This organotypic model includes human alveolar-like epithelial cells (H441), human lung fibroblasts, and human lung microvascular endothelial cells (HULEC). We hypothesized that air pollutant exposure of the H441 cells would initiate the onset of a pro-thrombotic state in the HULEC. To test this, we exposed H441 cells to the ubiquitous air pollutant, diesel exhaust particulates (DEP), and investigated the effect of this trans-alveolar exposure (TA-DEP) on the underlying HULEC. TA-DEP exposure induced expression of anti-oxidants such as heme oxygenase 1 and NAD(P)H dehydrogenase [quinone] 1, increased nuclear factor erythoid-2 related factor (NRF2) protein, and reduced glutathione redox potential in the HULEC. Concurrently, decreased expression of the endothelial fibrinolytic and anti-coagulant genes, tissue-type plasminogen activator, plasminogen activator urokinase, and thrombomodulin, and increased expression of the procoagulant gene, coagulation factor III occurred in the HULEC. These data suggest that TA-DEP exposure induces redox dysfunction and an endothelial pro-thrombotic profile in the ACR. We conclude that redox dysfunction and pro-thrombotic activation in the capillary beds of the ACR may be critical initiation steps of API-T. Data from this model can help develop intervention strategies against API-T and can encourage the development of organotypic models resulting in a reduction of animal testing. This does not reflect EPA policy.
Sheri Bloch – PhD Student – Université de Montréal
Eva Vitucci – PhD Student – University of North Carolina, Chapel Hill
Eva has a B.S. in Microbiology from the University of Florida and is working on her PhD in the Curriculum in Toxicology and Environmental Medicine at the University of North Carolina – Chapel Hill.
Webinars – 2020
December 17th, 2020 – Medical Device Assessment: Updates for Thrombogenicity and Skin Irritation
Thursday, December 17th, 2020
11:00-12:30 AM US ET// 5:00 PM – 6:15 PM CET
In vitro methodology for medical device material thrombogenicity assessments
Presenter: Michael F. Wolf, PhD, Medtronic
In vivo vascular implant models are currently used to assess implant material thrombogenicity for medical devices. We report an in vitro thrombogenicity assessment methodology where test materials alongside positive and negative controls were exposed to fresh human blood, using gentle-agitation test tube and pulsatile-flow closed-loop models. We report that: thrombogenicity was strongly dependent on several experimental variables, and in vitro to in vivo case comparisons showed consistency in thrombogenicity rankings on a range of materials. In vitro methods using fresh human blood are scientifically sound and cost effective compared to in vivo methods for screening thrombogenicity.
In Vitro Irritation Testing for Medical Devices: A Progress Update
Presenter: Kelly P. Coleman, PhD, DABT, ERT, Medtronic
Assessment of skin irritation is an essential step in the biocompatibility evaluation of medical devices. Two international validation studies were conducted to evaluate reconstructed human epidermis (RhE) models as alternatives to the rabbit skin irritation test. First, extracts of four irritant polymers and three non-irritant controls were used with two types of RhE tissues. Both tissue types identified virtually all the irritant polymer samples, indicating that RhE tissue models can detect the presence of strong irritants at low levels in dilute medical device polymer extracts. The second study used two other types of RhE tissues and produced similar results. It was concluded that RhE models are suitable replacements for the rabbit skin irritation test to support the biocompatibility evaluation of medical devices, and in 2020 a new ISO 10993-23 standard was finalized which states that the use of RhE tissues is preferable to rabbits.
Register here: https://register.gotowebinar.com/register/9037618754836657166
November 30th, 2020 – Development of a Bayesian Network Model for Predicting Fish Acute Toxicity from Fish Embryo Toxicity Data
Monday, November 30 th, 2020
10:00-11:00 AM US ET// 16:00-17:00 CET
Presenter: Adam Lillicrap, Norwegian Institute for Water Research
Reduction of animal testing, wherever possible, is required by legislations such as the EU Directive 2010/63/EU. Fish Embryo Toxicity (FET- OECD TG236) testing has been proposed to be an alternative to the juvenile acute fish toxicity test (AFT- OECD 203). However, FET data are not yet accepted as a replacement to the AFT test for certain regulatory purposes such as REACH. The European Chemicals Agency (ECHA) recommended that a weight-of-evidence (WoE) approach was needed for FET data before it could possibly be used in place of AFT data. Therefore, a Bayesian network (BN) model has been developed to incorporate multiple lines of evidence, in combination with FET data, to predict AFT. Bayesian networks are increasingly being used in ecological risk assessment because they can integrate large amounts of data and other information sources to produce discrete probability distributions, and predict the probability of specified states.
The objectives of this study were:
1) To develop and evaluate a BN model for predicting toxicity of substances to juvenile fish from embryo toxicity data in combination with other relevant information;
2) To apply the BN model in a WoE approach which can support replacing juvenile fish toxicity testing with embryo toxicity testing.
The BN model correctly predicted the AFT toxicity level for 14 substances, and gave lower toxicity for 6 substances. For the 6 substances with an incorrect prediction, 5 substances (2,4-Dichlorophenol, 4-Chlorophenol, Malathion, Naphthalene, Prochloraz) were less toxic to fish than to daphnids or algae, hence the AFT data would not drive the environmental risk assessment for those substances. In the case of 1 of the substances (Juglone), the AFT test was less sensitive than the FET data.
September 24, 2020 – Phenotypic profiling for high-throughput chemical screening at the U.S. EPA
September 24th, 2020
10:00-11:00 AM US ET// 16:00-17:00 CET
Presenter: Johanna Nyffeler, ORISE Fellow with US EPA
The Center for Computational Toxicology & Exposure (CCTE) at U.S. EPA developed a blueprint for utilization of new approach methodologies (NAMs) in computational toxicology. The tiered approach relies on high-throughput profiling assays in the first step in characterizing the biological activity of chemicals. Chemicals are run in concentration-response in the assays for two purposes: (1) To derive a potency estimate for chemical bioactivity. This in vitro potency estimate can then be used to prioritize chemicals and/or compare the bioactivity to exposure estimates. (2) To gain information about putative mechanisms-of-actions. Depending on the mechanisms-of-action, different second and third-tier assays may then be performed to confirm hypothesized bioactivity. CCTE currently has two such profiling assays: High-throughput transcriptomics and imaging-based high-throughput phenotypic profiling (HTPP). In the webinar, I will outline our efforts to achieve these two purposes for HTPP assay. For HTPP, we are using an assay called ‘Cell Painting’, that labels multiple cellular organelles (nucleus, nucleoli, endoplasmic reticulum, golgi, actin skeleton, plasma membrane, mitochondria) to measure changes in cell morphology in response to chemical treatment. We have operationalized the assay for 384 well plates to run concentration-response screenings and extract 1300 features on a single-cell level. To date we have screened > 1200 chemicals at 8 concentrations in human U-2 OS sarcoma cells. We have derived potency estimates (i.e. phenotype altering concentrations, PACs) for all active chemicals. For 303 chemicals, in vitro-to-in vivo extrapolation was performed to compare the potency estimates to available in vivo data. For 78% of the chemicals, the HTPP potency was within two orders of magnitude from the in vivo point-of-departure. Moreover, for 72% of chemicals, HTPP was comparable or more conservative than the in vivo point-of-departure. For each active chemical, a phenotypic profile was derived from the 1300 measured features. Profiles were then compared using Pearson correlation. Among the tested chemicals were 179 chemicals with target annotations in the RefChemDB database. We could show that for two pathways (retinoic acid pathway, glucocorticoid receptor), chemicals activating the same target also display high profile similarity. Moreover, by comparing all tested chemicals to the annotated chemicals, we identified five test chemicals with high profile similarity to retinoids. Of those, four were not previously identified as modulators of the retinoic acid pathway. To summarize, our results to date indicate that the HTPP assay can be used to derive potency estimates as well as some mechanistic information that can both be used for prioritization of chemicals. This abstract does not reflect U.S. EPA policy.
August 20, 2020 – PubMed Abstract Sifter: a literature informatics tool for chemical research
Thursday, August 20th, 2020
10:00-11:00 AM US ET// 16:00-17:00 CET
Presenter: Nancy C. Baker, Leidos, Inc. and US EPA
Assessing and understanding chemical effects requires assembling information from a wide variety of sources, including millions of articles in the biomedical literature. Literature informatics approaches can help researchers make use of this information in more effective ways. We present the PubMed Abstract Sifter, a freely available literature tool from the US Environmental Protection Agency. With the Abstract Sifter, researchers can easily retrieve and triage citations from PubMed and visualize the literature landscape for a set of chemicals. The tool is supplied with template queries that facilitate the exploration of mechanistic information by using the language of Adverse Outcome Pathways (AOPs) and Key Characteristics of Carcinogens.
This abstract does not necessarily represent US EPA policy.
Registration is now open: https://attendee.gotowebinar.com/register/4664129833149496844
July 8, 2020 – Human biology-based approaches for COVID 19 therapeutics
Wednesday, July 8, 2020
11:00-12:30 EDT / 17:00-18:30 CET
First speaker: Malcolm Wilkinson, Kirkstall
Title: Building more physiological models of human disease
Quasi Vivo® Systems are a way to introduce air and media flow over in vitro cell cultures and can be used to create multi-cell or multi-organoid models for the study of disease. Current projects specifically focused on COVID-19 include: 1) development of a model that mimics infection of by SARS-CoV-2 with natural flow of lymph and blood in the body and assess responses to the entry of SARS-CoV-2 in cells from the respiratory tract and responses on circulating blood cells from the immune system, 2) building a multi-tissue model which replicates human obesity and how different tissues communicate with each other in diseases like SARS-COVID19, and 3) improving our understanding of how cigarette smoke increases susceptibility to SARS-CoV-2 infection in the lungs and help in developing a therapy for prevention and treatment.
Second speaker: Samuel Constant, Epithelix
Title: 3D Human epithelial models to study SARS-CoV-2 pathogenesis
The respiratory system is the main entry portal of SARS-CoV-2 which infects initially and principally the airway epithelia. Epithelix has developed standardized air-liquid interface 3D human airway epithelial cultures from nasal or bronchial (MucilAir™) and small-airway (SmallAir™) origins. These epithelial models closely mimic the morphology and function of the native tissues and have been used for the development of antivirals against influenza, rhinoviruses, respiratory syncytial virus, amongst others. This talk will highlight how these reconstituted human airway epithelial models can be used to characterize viral infection kinetics, tissue-level tropism and transcriptional immune signatures induced by SARS-CoV-2. Relevance of these models for the preclinical evaluation of antiviral candidates will also be addressed in the context of repositioning of marketed drugs or evaluation of novel therapies and combinations delivered systematically or through aerosol therapy.
Registration link: https://attendee.gotowebinar.com/register/2314631813250734349
June 9, 2020 – The Use of Machine Learning and Artificial Intelligence in Toxicology and Risk Assessment
Tuesday, June 9, 2020
10:00 AM US ET / 16:00 CET
Presenter: Timothy E H Allen, Research Scientist, Willis Group, MRC Tox
Register Now: https://register.gotowebinar.com/register/1289551624711993102
May 26, 2020 – International computational collaborations for predictive toxicology
Tuesday, May 26, 2020
11:00 AM US ET / 17:00 CET
Presenter: Kamel Mansouri, Integrated Laboratory Systems, Inc.
Humans are exposed to an ever-increasing number of chemicals, but only a fraction of these have been evaluated for potential risks to human health and the environment. Thus, both regulators and manufacturers need rapid and efficient approaches to evaluate the potential toxicity of thousands of chemicals already in commerce and others in development. Advances in information technology and machine learning have fostered the development of in silico approaches that leverage the relationships between chemical structures and their biological activities. However, individual predictive computational tools are associated with certain limitations, and they are only as good as the input data upon which they are built. To address these challenges, international consortia involving over 100 scientists from governmental agencies, academia, and industry were formed to collaboratively develop in silico tools for predicting chemical toxicity. These consortia have successfully concluded three projects: the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP), the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA), and the Collaborative Acute Toxicity Modeling Suite (CATMoS). These projects used data from both the published literature and the ToxCast/Tox21 programs curated to meet defined quality specifications. Limitations of individual modeling approaches were overcome by establishing consensus models that leveraged each model’s strengths. The resulting consensus models have been used to screen hundreds of thousands of chemicals from the U.S. Environmental Protection Agency’s (EPA’s) DSSTox database. These models are freely available for further use through the OPEn structure-activity/property Relationship Application (OPERA), as an open-source standalone application and by querying the EPA’s CompTox chemistry Dashboard (https://comptox.epa.gov) and NTP’s Integrated Chemical Environment (https://ice.ntp.niehs.nih.gov).
Register Now: https://register.gotowebinar.com/register/4739262759308645647
 Mansouri, K. et al. EHP: https://doi.org/10.1289/ehp.1510267
 Mansouri K. et al. J Cheminform: https://doi.org/10.1186/s13321-018-0263-1.
 Kleinstruer N.C. et al. Comput Toxicol: https://doi.org/10.1016/j.comtox.2018.08.002
 Mansouri, K. et al. EHP: https://doi.org/10.1289/EHP5580
April 30, 2020 – Use of New Approach Methodologies for cosmetic safety assessment without animal testing
Thursday, Apr 30, 2020
11:00 AM US ET / 17:00 CET
Recent advances in chemical safety assessment now allow the complete evaluation of personal care products without the use of animals. Exposure based approaches and hypothesis-driven data generation form the basis of non-animal cosmetic safety assessments. The safety assessment approach begins with problem formulation and evaluation of existing information before considering the development of targeted testing approaches. Assessment tools, often described as New Approach Methodologies (NAMs), can include computational models and human-relevant in vitro assays which are applied in combination to provide information on ingredient hazard and risk assessment. Finally, these disparate types of information are integrated and weighted in a transparent assessment that captures uncertainty. Each presentation in this webinar will cover different aspects of this decision process.
11:00 Introduction: Hypothesis led safety assessment of cosmetics,
Catherine Willett, Humane Society International
11:10 Exposure based safety assessment of cosmetics,
Corie Ellison, Procter and Gamble
11:25 The application of in silico models to support decision making in toxicology: QSAR, informatics, pathway modelling, uncertainty,
Chris Barber, Lhasa, LTD
11:40 In vitro approaches to cosmetic safety assessment
Paul Walker, Cyprotex Discovery Ltd
11:55 Integration of new approach methodologies for cosmetic safety decision making
Matt Dent, Unilever
11:10 Q & A
For more information about the project, see AFSAcollaboration.org/Cosmetics
March 11th, 2020 – ASCCT Award Winners Webinar – Toxicological mechanistic inference: Generating mechanistic explanations of adverse outcomes
Wednesday, March 11th, 2020
11:00 AM US ET / 17:00 CET
Presenter: Ignacio J. Tripodi, PhD Candidate in Computer Science / Interdisciplinary Quantitative Biology, University of Colorado, Boulder
Registration Link: https://attendee.gotowebinar.com/register/9200492703200567307
Government regulators and others concerned about toxic chemicals in the environment hold that a mechanistic, causal explanation of a mechanism of toxicity is strongly preferred over a statistical or machine learning-based prediction by itself. We thus present a mechanistic inference framework, which can generate hypotheses of the most likely mechanisms of toxicity for a specific chemical and cell type, using gene expression time series on human tissue and a semantically-interconnected knowledge graph. We seek enrichment in our manually-curated list of high-level mechanisms of toxicity (e.g. “Triggering of caspase-mediated apoptosis via release of cytochrome C”, or “Mitochondria-mediated toxicity by inhibition of electron transport chain”), represented as causally-linked Gene Ontology concepts.
Our knowledge representation is an extension of the PheKnowLator knowledge graph. It consists of an integration of concepts from multiple ontologies (GO, PRO, HPO, ChEBI, PATO, DOID, CL), as well as relevant concepts from Reactome, Uniprot, the cellular toxicogenomics database (CTD), and the AOP Wiki. The expression assays were obtained from the Open TG-Gates, CarcinoGenomics, and other projects, consisting of human liver, kidney, and lung, bronchial, buccal, and nasal epithelial cells exposed to a sizeable number of chemicals that elicit different mechanisms of toxicity. Both our knowledge graph and experimental transcriptomics data are human-centric. Besides predicting the most likely mechanisms of toxicity from the transcriptomics assays, we generate putative explanations based on the most significant genes at each time point with known links to their corresponding mechanism steps. This provides a transparent, possible explanation for the mechanisms of toxicity, that would help a researcher’s decision-making process and aid further experimental design. Furthermore, we were able to experimentally validate our mechanistic predictions for some chemicals without an established mechanism of toxicity.
Co-expression Network Analysis to Identify Heterogeneity Between the Breast Cancer Cell Line MCF-7 and Human Breast Cancer Tissues
February 25th, 2020 – Moving away from animal testing for acute inhalation toxicity testing
Tuesday, February 25th, 2020
10:00 AM US ET / 17:00 CET
Presented by Emilie Da Silva, PhD student, Technical University of Denmark/National Research Center for the Working Environment, Denmark
Registration Link: https://attendee.gotowebinar.com/register/4278909332419455243
ABSTRACT: Testing for acute inhalation toxicity is required for chemicals manufactured or imported at tonnages ≥ 10 tons per year (Commission Regulation (EC) No 440/2008) and for biocides (Regulation (EU) No 528/2012) and plant protection products (Regulation (EU) No 283/2013) before they are allowed on the market. Currently, three OECD Test Guidelines are available (TG 403, TG 436, and TG 433), all based on the exposure of rodents to the substance of interest for up to 4 hours. The use of animals for toxicological evaluation does not come without challenges. Animal experiments are costly and time consuming. It is estimated that the turnaround time for carrying out an acute inhalation test is 3 to 4 months. Besides, using rodents in order to predict the toxicity of a compound in humans is arguable given the differences in the features of the respiratory tract. The development and the validation of alternative methods in chemico, in vitro and/or in silico are needed. To do so, the mechanistic understanding of the toxicity of inhaled chemicals is key.
An innovative in vitro method for acute inhalation toxicity will be presented. This cell-free method is based on the monitoring of lung surfactant function. Indeed, the lung surfactant layer in the alveoli is the first barrier that inhaled compounds will encounter when they reach the respiratory region in the lungs. The correlation between the inhibition of the lung surfactant function and the decrease in tidal volume in mice was shown with a variety of compounds including excipients for drug formulation, and impregnation spray products. During this webinar, the method will be introduced and explained, and case studies using different chemical groups will be presented.
January 21, 2020 – ESTIV Award Winners Webinar – Role of In Vitro Mechanistic Data for the Assessment of Endocrine Disruptors in the Regulatory Context
Presented by Dr. Laura Escrivá, Assistant Professor, University of Valencia, Spain.
Tuesday, January 21st, 2020 at 4:00 pm CET
Available online at: https://www.ascctox.org/webinars/eVmBMbpCMaG5/61
ABSTRACT: Scientific EU criteria and guidance from ECHA and EFSA to identify substances with Endocrine Disruptor (ED) properties have recently been implemented for plant protection products and biocidal products. The ECHA/EFSA guidance, mainly addressing EATS (estrogen, androgen, thyroid, steridogenesis) modalities, provides a protocol for ED identification, which includes the evaluation of both the adverse effects and the endocrine activity, by applying weight of evidence analysis.
The assessment of the endocrine activity requires in vitro mechanistic data providing information on the mechanism through which a substance could be considered endocrine active (e.g. by binding to and activating a receptor or interfering with hormone production). Moreover, when potentially endocrine-related adverse effects and endocrine activity are identified, the biological plausibility of the link between endocrine activity and the endocrine mediated adversity should be established by a mode of action analysis. The webinar will focus on the different steps for ED identification according to the ECHA/EFSA guidance illustrating how essential it is the in vitro data for ED assessment under EU regulatory context.
January 21, 2020 – ESTIV Award Winners Webinar – A battery of animal-free in vitro assays for evaluating prenatal developmental toxicity potency of highly complex petroleum substances
Presented by Dr. Lenny Kamelia, Division of Toxicology, Wageningen University and Research, The Netherlands.
Tuesday, January 21st, 2020 at 4:00 pm CET
Available online at: https://www.ascctox.org/webinars/eVmBMbpCMaG5/61
ABSTRACT: REACH legislation requires prenatal developmental toxicity (PDT) testing for substances registered at a volume of >100 tonnes/year, which also applies to petroleum substances (PS). Given that i) PDT testing is one of the most complex, and animal- and resource-intensive regulatory requirements for substances produced at >100 tonnes/year, and ii) PS are highly complex materials (UVCBs), the development of alternative non-animal based testing strategies for PS poses huge challenges. Some PS contain high concentrations of polycyclic aromatic hydrocarbons (PAHs) and we hypothesize that PDT as observed for some PS is caused by certain types of PAH present in these products. To this purpose, DMSO-extracts of 9 PS (varying in PAH content; from 5 different product categories), 1 highly refined base oil (HRBO) (containing no PAHs), and 2 gas-to-liquid (GTL) products (devoid of PAHs) were tested in a battery of in vitro assays, including the embryonic stem cell test (EST), the zebrafish embryotoxicity test (ZET), and the aryl hydrocarbon (AhR) CALUX assay. All DMSO-extracts of the PS, but not of the HRBO and GTL, induced concentration-dependent PDT as quantified in the EST and ZET, with their potency being proportional to their 3- to 7-ring PAH content. Moreover, all PS extracts also showed AhR-mediated activity in the AhR CALUX assay, suggesting a role of the AhR in mediating the observed PDT by these substances. Combining the results of the EST, ZET, AhR CALUX assay, and the PAH content, ranked and clustered the test compounds in line with their in vivo PDT potencies. In conclusion, our battery of in vitro assays, consisting of the EST, ZET and AhR CALUX assay, is able to evaluate and differentiate the PDT potency of highly complex PS, within and among categories. The results are also in concordance with our hypothesis on the role of specific groups of PAHs present in some PS for the observed PDT induced by these substances.
Archived Webinars – 2019
Deep Learning in Toxicity Prediction: Reasons for Use and Possible Applications
Presented by Dr. Suman Chakravarti, Chief Scientific Officer, MultiCASE
December 4, 2019 at 4:00 pm CET
ABSTRACT: Use of deep learning is increasing in solving different problems in computational toxicology and QSAR methodology in general. However, it is important to recognize the strengths of deep learning techniques in order to get the best out of them.
This webinar will focus on different aspects of computational toxicity assessments that can be improved using deep learning techniques beyond just increasing the accuracy of the predictions. For example, building scalable QSARs using big data, eliminating the use of precomputed descriptors from QSARs, expanding domain of applicability of QSARs and identification of toxicity alerts using deep learning techniques. In addition, available free tools and different types of deep learning architectures that are relevant to toxicity assessments will be discussed with the aid of case studies.
December 4th Webinar, Deep Learning in Toxicity Prediction: Reasons for Use and Possible Applications, presented by Suman Chakravarti, Chief Scientific Officer, MultiCASE, has been posted online and is now available for viewing at your convenience.
The pros and cons of 3D in vitro cultures of liver fibrosis
Presented by Leo van Grunsven, Vrije Universiteit Brussel.
November 4, 2019 at 4:00 pm CET
ABSTRACT: Chronic liver disease is the major cause of progressive liver fibrosis which, in turn, leads to cirrhosis of the liver. One major obstacle in the development of efficient therapies is the lack of robust and representative in vitro models of human liver fibrosis to aid in understanding the basic mechanisms of the disease and in the development phase of pharmaceuticals. The aim of this presentation is to give some background on the mechanisms involved in liver fibrosis development and why our work is based on the central hypothesis that liver fibrosis in vitro cannot be studied using only hepatic stellate cells (HSCs)–the main producer of scar tissue during fibrosis. I will present and discuss some results and problems we faced while developing an in vitro liver fibrosis model. We established a model in which HepaRG cells (Biopredic) were co-cultured with either in-house isolated HSCs or in-house differentiated induced pluripotent stem cell derived HSCs. In both cases, exposure to hepatotoxins resulted in hepatocytic damage and consequent HSC activation. We now work on a model using only primary mouse HSCs and hepatocytes. I will also discuss some of our work aiming at developing more complex primary mouse co-cultures for liver disease modeling and briefly address the work of other groups that reported on such complex in vitro culture systems.
The November 4th Webinar, The pros and cons of 3D in vitro culture models of liver fibrosis, presented Prof. Leo A. van Grunsven, Vrije Universiteit Brussel, has been posted online and is now available for viewing at your convenience.
Translational challenges in in vitro nephrotoxicity model
Presented by Roos Masereeuw, Div. Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands.
October 22, 2019 at 4:00 pm CET
ABSTRACT: Adverse effects caused by exposure to foreign compounds, including drugs, often involve the kidney. In fact, 14 to 26% of the acute kidney injury events reported can be related to drug-induced kidney injury. Although acute damage to the kidney may be reversible, depending on severity, 30% of the patients develop structural renal dysfunction leading to chronic kidney disease eventually progressing into end-stage kidney disease. Early prediction of adverse effects such as drug interactions and renal toxicity is therefore imperative for clinical practice and for the development of new and safe drugs. Current in vitro assays do not accurately allow such prediction, predominantly due to inadequate preservation of the organs’ microenvironment. The kidney epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and responsiveness to environmental signals influencing cell proliferation, migration and differentiation. This presentation will provide an overview of advances in 3D cultures of human renal cells and organoids in microfluidics, and in particular kidney tubules, thereby improving physiological performance of the tissue. These microphysiological systems have great potential for drug screenings and provide novel alternative strategies for the prediction of renal drug disposition and safety assessment in a human-specific context. However, knowledge gaps in quantitative translation of renal drug disposition from microphysiological systems still exist and will be discussed.
Developmental neurotoxicity evaluation: on the road to regulatory acceptance
Presented by Prof. Ellen Fritsche, Leibniz Research Institute for Environmental Medicine-Germany
August 28, 2019 at 4:00 PM CET
Nerve-on-a-chip platform for assessing chemotherapy-induced peripheral neuropathy
Presented by Dr. Lowry Curley, AxoSim Inc.
September 17, 2019 at 5:00 PM CET:
Using Quantitative Systems Toxicology (QST): Improving the safety of drugs while reducing animal testing (July 2019) Presenter: Paul B. Watkins, M.D., University of North Carolina – Chapel Hill
GARD™air – An in vitro assay to test for respiratory sensitizers using genomic biomarkers and machine learning (June 2019) Presenter: Joshua Schmidt, SenzaGen Inc., USA Co-author: Andy Forreryd, SenzaGen AB, Lund, Sweden
EPA computational tools (May 2019)
The CompTox Chemicals Dashboard and Generalized Read Across
Presenters: Antony Williams and Grace Patlewicz, EPA
Automated and Integrated Analysis Workflow for Adverse Outcome Pathway Identification, Hypothesis Generation and Risk Assessment (April 2019) Presenters:
Noffisat O. Oki (1) and Tatyana Doktorova (2)
1Edelweiss Connect Inc, Durham, NC, USA
2Edelweiss Connect Gmbh, Basel, Switzerland
Advancing tools for predictive toxicology (March 2019) Title: Establishment of bile duct tubular structure mimicking the intrahepatic bile duct morphogenesis for an in vitro bile recovery
Presenters: Astia Rizki-‐Safitri, Marie Shinohara, Minoru Tanaka, and Yasuyuki Sakai
Title: Generation of recombinant human anti-diphtheria toxin neutralizing antibody to replace equine sera
Presenters: Esther Wenzel, Paul Stickings, Jeffrey Brown, Thea Sesardic, Androulla Efstratiou, Michael Hust
Title: Development and Use of Adverse Outcome Pathway (AOP) Networks to Support Assessment of Organ Level Effects
Presenters: Nicoleta Spinu, Mark TD Cronin, Steven J. Enoch, and Judith C Madden
Combining biological and computational approaches (February 2019) Presenter 1: Daniel Russo, Rutgers University
Title: Developing Mechanism-Based Animal Toxicity Models: A Chemocentric Approach Using Big Data
Presenter 2: Sudin Bhattacharya, Michigan State University
Title: Integrating Genomics and Epigenomics into Predictive Toxicology of the AH Receptor
Nanoceramic pulmonary toxicity & reproducible cell line technology (January 2019)
Award Winners Series: Nanoceramic pulmonary toxicity & reproducible cell line technology
Jan 23, 2019 10:00 AM EST
Presenter 1: Maria João Bessa, PhD candidate, Portuguese National Institute of Health
Title: Pairwise toxicity evaluation of ceramic nanoparticles exposure in human alveolar epithelial A549 cells at submerged and air-liquid cultures
Presenter 2: Tom Wahlicht, PhD, InSCREENeX GmbH
Title: Reproducible in vitro toxicology testing using functional immortalized cells