Virtual Continuing Education Courses

CRISPR-Cas-based technologies have revolutionized science by significantly decreasing the time, money, expertise, and labor required to implement gene editing. Thus, this approach is becoming routine in many laboratories as a facile method to alter the genome. And yet, CRISPR-based methodologies continue to evolve. Recent publications demonstrate that CRISPR gene editing can be expanded in new directions to widen the utility and potential applications of this technology. The first presentation in this course will provide an overview of the latest developments in CRISPR-Cas-based techniques, with a focus on new Cas9 variants with new and expanded capabilities. The first presentation also will cover the new field of RNA targeting and the use of pooled CRISPR libraries with single cell transcriptomics to characterize complex phenotypes. The second presentation will focus on the use of CRISPR-Cas9-based screens from a toxicologist’s perspective. Specifically, this presentation will discuss how such screens can be used to gain a detailed, mechanistic understanding of a toxicant’s effect as well as the role of specific genes. Overall, this course is designed to provide an overview of the most recent advances in CRISPR-based technologies as well to provide some insight into future uses.

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No longer are eye drops the only way to treat the eye; the emergence of novel therapeutic and development approaches for ocular indications has impacted how we design toxicology assessments, select species, and perform toxicity evaluations. Additionally, the structural complexity of the eye as well as the unique aspects of ocular dose-administration routes require continued refinements of ocular evaluation techniques and assessment strategies. The goal of this course is to provide toxicologists with a broad overview of highly specialized ocular anatomy, current ophthalmic diagnostic techniques, evolving histopathological assessment strategies, and thought-provoking ocular drug development strategies, including case studies. The first speaker will open the session with an detailed overview of ocular anatomy complexity, focusing on unique features of the eye and critical anatomical and physiological features that may influence or impede a drug’s efficacy and safety in human patients. The speaker also will discuss novel routes of drug administration in ocular drug development. The second presentation will tune in to gold-standard, in-life ophthalmic diagnostic techniques with selected case examples showing how modern ocular diagnostic equipment can be used to prove multifactorial questions. This presentation also will touch upon recent efforts at harmonization of ocular finding nomenclature and clinical record-keeping lexicon in preparation for SEND (Standard for Exchange of Nonclinical Data) requirements dictating reporting of ocular toxicology studies. The third talk will focus on evolving strategies for histopathological assessment of ocular tissues, which will include key points to consider when processing the eye to ensure a thorough examination of key structures of the globe as well as the effect of factors such as the route of administration and the formulation or character of the therapeutic candidate on effective examination of the eye. The last presentation will highlight unique nonclinical safety challenges and considerations during ocular drug development using case studies to push our assumptions of what is the best way to evaluate the safety of ophthalmic therapeutics.

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Computational toxicology is rapidly accelerating our ability to develop methods for predicting chemical properties and chemical-mediated effects, both in the environmental chemical space and in the area of drug development. With frequently updated tools and approaches, overwhelming feedback suggests that more training is needed to help all toxicologists understand the fundamental approaches, use available tools and databases, and interpret outputs. This CE course is designed to offer an introductory-level foundation for leveraging some widely accepted approaches and demonstrate how to use open-source tools and resources to make use of these methods. Course participants across all sectors, ranging from students to career toxicologists, should walk away with the confidence to use the resources presented for computationally characterizing and predicting chemical-elicited toxicity. In addition to gaining familiarity with basic computational toxicology concepts, participants will gain insight into what makes an approach useful for research projects versus which are ready for potential regulatory applications. The first speaker will help lay a foundation for how chemicals are “interpreted” computationally, explaining how chemical structures are leveraged for subsequent analyses (i.e., fingerprinting and its use for read-across). Building on these concepts, the second speaker will provide a thorough example of how to use the US Environmental Protection Agency (US EPA) CompTox Chemicals Dashboard, which provides data for nearly 900,000 chemicals and drugs. Attendees will learn how to assess the confidence in available data, as well as learn how to use the tools available in the dashboard for predicting chemical toxicity and download pertinent data, including mechanistic information, exposure data, animal toxicity doses, and much more. The third presentation will provide a demonstration to empower course attendees in using the Integrated Chemical Environment (ICE), an interactive tool that contains in vitro to in vivo extrapolation workflows that users can leverage to conduct analyses themselves, as well as provides curated in vivo and in vitro datasets that can be used to evaluate predicted toxicology outcomes. The fourth presentation will steer the course further into the realm of biological interpretation, describing how toxicogenomics data and literature mining underlying the Comparative Toxicogenomics Database (CTD) can be utilized to computationally characterize chemical mode of action and provide insight into toxicity mechanisms. The last speaker will introduce Sysrev, a collaborative computational systematic review tool to extract pertinent data from literature, incorporating approaches such as machine learning and metadata tagging. Overall, course attendees will gain a fundamental understanding of approaches underlying the most widely used computational toxicology methods, as well as learn to use publicly available, open-source tools that apply these methods.

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Quantifying dose-response relationships to evaluate the toxicity of environmental chemicals is a key step in human health risk assessment and has evolved substantially in recent years. In addition to fundamentally developing a dose-response curve and estimating a dose level that results in a predetermined critical effect, recent advances in toxicology and modeling strategies enable dose-response assessment to more comprehensively and quantitatively address uncertainty and human variability. The purpose of this course, to be delivered by a mixed group of experts from academia, government, and industry, is to provide participants an overview of the cutting-edge modeling strategies employed in dose-response assessment to quantify uncertainty and variability. The first presentation will introduce the benchmark dose (BMD) methodology and its utilities to quantify various sources of uncertainty in dose-response modeling with a demonstration of the Bayesian BMD modeling system. The second speaker will present an overview of the principles and recent applications of probabilistic dose-response assessment approaches developed under the WHO/IPCS guidance to address uncertainty and variability in quantitative risk assessment. The third presentation will provide an overview together with case examples of Diversity Outbred (DO) mouse population-based in vitro systems to demonstrate a data-driven probabilistic approach to derive a chemical-specific uncertainty factor for inter-individual variability. The last speaker will introduce how to predict population distributions of toxicokinetic-relevant physiological quantities that NHANES does not measure based on the measured counterparts using the HTTK-Pop R package that incorporates population variability in high-throughput toxicokinetic modeling. Throughout the course, use of and applications to in vitro and high-throughput testing systems will be highlighted, including their relevance to in vitro to in vivo extrapolation (IVIVE).

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In the current landscape of drug development and investigation of environmental chemicals, many personnel with toxicology backgrounds find themselves overseeing not only preclinical safety assessments but also in vitro xenobiotic metabolism and interaction studies. Therefore, the goal of this course is to provide attendees with practical perspectives from experts in the field on the approaches and techniques that are available to address the important aspects of xenobiotic metabolism. The first presentation will focus on the experimental design and interpretation of data obtained from studies of in vitro inhibition of cytochrome P450 (CYP) and other xenobiotic-metabolizing enzymes. In contrast, the second presentation will focus on the experimental design and interpretation of data obtained from studies of in vitro induction of CYP and other xenobiotic-metabolizing enzymes. The third talk will broaden considerations of xenobiotic metabolism, including assessment of the toxicological burden of reactive metabolites, and the experimental design and interpretation of data obtained from studies of in vitro reaction phenotyping techniques in human liver microsomes and other test systems derived from humans or toxicologically relevant species. The fourth presentation will discuss in vitro approaches for determining the potential for xenobiotics to be substrates or inhibitors of major transporters that are of regulatory interest and interpretation of the data obtained from these studies. The final presentation will discuss the practical implications of the in vitro approaches discussed and the current regulatory thinking on their applicability to all xenobiotics to which humans are exposed. The overarching objective of this course is to provide attendees with a solid foundation in commonly used methods to enable the design, execution, and interpretation of rigorous and reproducible in vitro xenobiotic metabolism and interaction studies that will withstand regulatory scrutiny and avoid common pitfalls. This course will benefit those whose toxicological interests are expanding to include in vitro xenobiotic metabolism, as well as professionals responsible for appraising or evaluating in vitro xenobiotic metabolism, interaction studies, and other ADME data for internal decision-making, risk assessment, or submission to various regulatory agencies.

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Recent shifts in the global regulatory landscape to consider the use of nonanimal testing methods have led to significant advances in the development of alternative test methods to replace, reduce, and refine animal use. The term new approach methodologies (NAMs) broadly describes any nonanimal technology, methodology, approach, or combination that can be used to provide information on chemical hazard and risk assessment. With new opportunities comes new challenges, such as validation of test results, understanding their applicability in different sectors and risk assessments, and global regulatory acceptance of these methods. Despite these challenges, the development, use, and acceptance of these predictive toxicology methods is on the rise. There is a wealth of knowledge and data that is being generated with NAMs; however, there are questions on when, how, and where can we use these NAMs. This CE course will provide an overview of NAMs along with case studies where they are being used or could potentially be used for regulatory risk assessment. The speakers will present on (1) chemical-biological data and analysis tools (Tox21/ToxCast) and examples where high-throughput screening (HTS) methods have been approved for use in regulatory decision-making; (2) read-across approaches and their use in regulatory risk assessment; (3) use of evidence maps and systematic reviews and case studies with a focus on application of each to regulatory risk assessment; (4) use of the adverse outcome pathway (AOP) including most well-developed examples of AOP-supported decision processes for evaluating skin sensitizing potential and a computational model to predict the likelihood of reproductive impairment based on aromatase inhibition; and (5) concepts underpinning Integrated Approaches to Testing and Assessment (IATA) and concrete examples for assessing developmental neurotoxicity (DNT) and carcinogenicity of chemicals used in a variety of sectors. Also, updates will be provided on IATA case study projects currently running at the OECD and a set of resources being developed to support IATA development, evaluation, and regulatory uptake. This course will be useful to those interested in understanding the regulatory application of NAMs.

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Cancer immunotherapy is an area that has been of great interest in the last few years as several new therapeutic approaches have shown encouraging results in the clinic and subsequent approvals. The normal immune system has a protective capacity against tumor cells (immunosurveillance), while tumors can employ mechanisms that can result in an insufficient supply of activated and/or antigen-specific T cells within the microenvironment (tumor evasion). To overcome this immune-evasive mechanism, T cells can be redirected and expanded within the tumor microenvironment. CD3 redirection, which leverages protein-based therapeutics to simultaneously bind CD3 on T cells and a tumor associated antigen (TAA) on tumor cells, and engineered T cell–based therapeutics to redirect T cells to TAAs are emerging as powerful ways to harness the immune system to combat malignancies.. The goal of this course is to provide the investigator with an overview of T cell redirection technologies and how to design a nonclinical safety strategy to understand safety liabilities. An overview of chimeric antigen receptor (CAR) T cells, T cell receptor (TCR) T cells, CD3 bispecifics, and immune mobilizing monoclonal TCRs against cancer (ImmTac) modalities will be provided. In addition, successful nonclinical safety strategies to support first-in-human clinical trials for these modalities will be shared. Overall, this course will provide a comprehensive overview of T cell redirection platforms, study design, and the challenges associated with these modalities.

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Inhalation is a major route of human exposure to airborne substances, and as such, there are regulatory and nonregulatory needs to assess the potential toxicity of inhaled substances. While the standard regulatory requirement is a rat inhalation toxicity test, anatomical and physiological differences between rodents and humans have led to substantial investment in the optimization of alternative approaches. These alternative approaches can be based on human mechanisms of toxicity, thus better protecting human health while reducing animal use. In this course, speakers from government, contract research organizations, academia, and NGOs, as well as method developers, will discuss progress and challenges associated with various approaches for inhalation toxicity testing. It will include an introductory overview, setting the stage for the remaining talks by discussing the currently used rat inhalation tests and how an alternative approach can be demonstrated to be a valid replacement. Other topics to be covered will be the use of cell culture systems, 3D reconstructed human tissue models, and human precision-cut lung slices, as well as the use of in vitro exposure devices for deposition of test chemicals. The final speaker will present a regulatory perspective on processes in place that allow for acceptance of alternative approaches for inhalation toxicity testing, highlighting a successful example. These presentations will explore the value of the air-liquid interface (ALI) for testing, advantages and limitations of different approaches, and case studies of the use of different model systems in both nonregulatory and regulatory paradigms. Overall, a course attendee should learn about the state-of-the-science of in vitro approaches for respiratory toxicity testing and gain insight into determining which method is most appropriate, depending on the test substance and purpose of the study. This course is aimed at scientists at all levels from industry, government, and academia.

COURSE BOOK

The male reproductive system develops in utero—in rats during mid-gestation and in humans during the second month of pregnancy—but does not fully mature until puberty. Exposure to xenobiotics (e.g., diethylstilbestrol and phthalate exposure) during any stage, particularly during development and maturation, can adversely affect a male’s reproductive potential and play a significant role in development of a diseased state. Understanding what normally happens at these critical stages of development can lend clues to determine when an exposure has happened, what tissues are affected, and if functional capabilities will be impacted. Defining potential effects is routinely performed with guideline reproductive and developmental experiments and in academia with focused studies; however, these assessments do not always include histopathology evaluations, and if they do, the rigor needed for select tissues may not be utilized. Inclusion of histopathology, especially during select stages, may help identify a pattern of toxicities, subtle effects of an endocrine-disrupting chemical, or lesions that can lead to future reproductive issues (e.g., infertility). This additional data can expand our capabilities in characterizing potential modes of action that result in functional changes. Thus, a field that did not routinely assess tissues in more than a functional manner is now exploring the utility of pathology evaluations at stages not previously studied (e.g., juvenile assessment of cell populations in the testes) and appreciating that these tools can assist in recognizing patterns of toxicity. Therefore, a full toxicological and histopathology assessment of the male reproductive tract may provide additional information on functional effects, assist in determining which part of the system was targeted and how to mitigate concerns, and, for select issues, provide an early read on potential problems. This course will cover development and maturation of the male reproductive tract, explaining impacts on function at different time periods (in utero, juvenile, and adult) and addressing the potential value of histopathology at both the juvenile and the adult stages. Case studies will be used to highlight the toxicological significance of the effects of xenobiotics on male reproductive system toxicity. Understanding patterns of toxicity (e.g., effects in organ weight linked with findings in other tissues or pathology findings observed in a young animal correlating to outcomes in an adult) and utilizing some of the newer techniques and protocols (e.g., fetal testis explants, biomarkers) will not only provide a better understanding of what endpoints are affected but also may provide us with the tools to design better studies and correlate findings at earlier stages with long-term functional effects. To this end, four speakers, each a world-recognized expert in male anatomy, development, reproduction, and/or pathology, will discuss functional assessments of the male reproductive tract and address the utility of pathology in male reproductive and development evaluations.