Continuing Education

Course Book

Room:
Room 205

Chair(s):
John Benitez, State of Tennessee Department of Health; and William Mattes, Independent Consultant.

While all toxicology addresses the adverse effects that agents have on living organisms, clinical and medical toxicology play unique roles not often encountered in traditional toxicology practice or research. These two subsets of toxicology focus on the immediate needs of patients suspected of being poisoned. These fields of toxicology require extensive knowledge of diseases and etiology as well as a thorough understanding of the effects of potential poisons, both of which are commonly used to make diagnoses. Clinical and medical toxicologists must consider three points—the substance involved, the toxic response, and the mechanism by which it occurs—in order to determine the best treatment options for each patient. This course will introduce participants to the basics of clinical and medical toxicology along with new and old tools that may be used by the clinical toxicologist.

Course Book

Supplement: Exercise 1 Case 1

Supplement: Exercise 1 Case 2

Supplement: Exercise 2 Case 1

Supplement: Exercise 2 Case 2

Supplement: Bessems et al 2017 for Package 1

Supplement: Bury et al 2021 for Package 2

Room:
Room 205

Chair(s):
Cecilia Tan, US EPA; and Alicia Paini, esqLABS GmbH, Germany.

Physiologically based kinetic (PBK) modeling predicts internal dose metrics by describing the critical physiological, physicochemical, and biochemical processes that determine the disposition of a chemical in an organism. Here, a general term “kinetic” is considered synonymous with pharmacokinetic (PK), toxicokinetic (TK), or biokinetic (BK). Traditionally, in environmental toxicology, the calibration of parameters in a PBK model and the evaluation of its predictive capability rely heavily on comparing model simulations with in vivo blood or tissue concentration data obtained from laboratory animals. However, the availability of in vivo data is limited to extensively researched chemicals, which impede the broader applications of PBK models by regulatory agencies. The recent paradigm shift toward using new approach methodologies (NAMs) to inform predictive approaches for chemical hazard and risk assessment necessitates the use of PBK models—developed and evaluated without data from live animals—to convert a bioactive concentration observed in cell-based toxicity assays to an equivalent human exposure level. In 2021, in order to keep pace with global efforts to develop and incorporate NAMs in chemical risk assessments, the Organisation for Economic Co-operation and Development (OECD) published a guidance document (GD) on characterizing, validating, and reporting PBK models without the use of animal data. This GD includes contextual information on the characterization and evaluation of PBK models in a regulatory context and highlights common in vitro and in silico approaches to parameterizing the models. The OECD GD provides a model reporting template and model evaluation checklist for evaluating the credibility of PBK models for their intended purposes. Adoption of the OECD PBK model GD is now encouraged when developing OECD Integrated Approaches to Testing and Assessment (IATA). This course offers training on key principles in the OECD GD. After a brief overview of the guidance, common, modern in vitro and in silico approaches for parameterizing a PBK model will be highlighted, as described in the second chapter of the GD. Next, various tools on how to evaluate the context, implementation, and scientific validity of a PBK model without using in vivo data will be presented, as recommended in the third chapter of the GD. At the end of the course, a hands-on exercise will give both novice and expert attendees an opportunity to apply their knowledge in evaluating example PBK packages. This course is designed for those involved in developing, applying, and promoting the acceptance of PBK models and those who seek to reduce/replace animal testing and incorporate more predictive mechanistic data in chemical hazard and risk assessment for human, animal, and environmental health. Attendees enrolled in this course will learn about the fundamental concepts underlying PBK modeling, data needs during model development, and commonly used metrics for model evaluation. These topics will be applicable to PBK models developed for drugs, industrial chemicals, biocides, pesticides, food additives, and chemicals in cosmetics and consumer products. These topics are also applicable to models developed for humans, laboratory test species, farm animals, and species of ecological relevance.

Course Book

Room:
Karl Dean Ballroom B1

Chair(s):
Satoko Kiyota, Genentech Inc.; and Marie Lemper, UCB S.A. Belgium.

Toxicologists who are fully integrated in early discovery project teams help enable efficient strategic decision-making around lead candidate selection, and are thus quite important. Last year, the Drug Discovery Toxicology Specialty Section hosted a Continuing Education (CE) course in order to focus on an overview of the drug discovery toxicology, from target assessment to identification of drug candidates. This year, the aim of this CE course is to provide an opportunity for toxicologists to gain insights into nonstandard toxicology contents (medicinal chemistry, ADME/pharmacokinetics, formulation development, and machine-learning) that can significantly impact safety outcomes and design of nonclinical safety strategies in the small molecule discovery space.

The first speaker will focus on the link between medicinal chemistry and safety liabilities. While the idea that chemical structures and physicochemical properties can drive safety liabilities has been recognized, toxicologists with limited professional training in medicinal chemistry may not feel empowered to influence medicinal chemistry design. This presentation will enable toxicologists to gain valuable insights into medicinal chemistry approaches in order to mitigate potential toxicophores and help identify chemical series with high potential.

The second speaker will discuss key in vitro ADME properties and liabilities, which can increase toxicity risks in vivo. Additional focus will be applied to how predicted pharmacokinetic profiles in humans can enable efficient compound triage from a safety perspective before progressing to in vivo toxicity assessments.

The third and fourth speakers will focus on interspecies metabolite comparison and formulation development, which are essential components in the design and conduct of nonclinical in vivo toxicity assessments. To ensure toxicology data from nonclinical species are vital to hazard identification and human risk assessment, the selected species should be relevant to human as far as primary pharmacology and metabolite profile. Additionally, it is imperative that robust exposure is demonstrated to ensure proper toxicological assessments, especially for non-oncology indications. Proper formulation selection is fundamental to address challenging properties of a compound and enable in vivo evaluation with desired exposure levels.

The last speaker will discuss how the emergence of machine learning can enable off-target hypothesis generation for an unexpected toxicity observed in vivo. Toxicologists should promptly identify any causes of unexpected toxicities and propose models to screen out compounds with unfavorable profiles if they are off-target-mediated. However, regardless of considerable time and financial investments, discovering the mechanism of toxicity may not be possible by empirical methods alone. Machine learning may help accelerate the generating of testable hypotheses.

The course will conclude with an interactive session to focus on how toxicologists can achieve diverse ranges of scientific expertise and ensure better decision-making early in the discovery stage. Overall, this course will inform toxicologists of new insights needed to utilize multidisciplinary tools and develop proactive safety paradigms that could reduce project delays and late-stage drug attrition. These concepts and approaches are generally applicable for predictive safety and investigative toxicology in any field, including academic research work.

Course Book

Room:
Room 207B

Chair(s):
Katherine Morton, Duke University; and Yvonne Will, Janssen: Pharmaceutical Companies of Johnson & Johnson.

Mitochondria are the central energy-producing organelle in the cells of most eukaryotes, though their roles within the cell expand far beyond bioenergetics. Recent work indicates that this dynamic organelle serves as a regulator of apoptosis, oxidative stress, calcium homeostasis, signal transduction, steroid hormone synthesis, and immunity among other pathways. As a result, mitochondria can alter cell and tissue function, which leads to aging, neurodegenerative disease, cardiovascular disease, inflammatory disorders, and increased cancer severity. However, despite increasing investigations into the non-bioenergetic roles of mitochondria, these areas remain critically understudied and misunderstood. For example, mitochondrial iron uptake plays a critical role in iron homeostasis and related hepatotoxicity. Similarly, mitochondrial dysfunction is increasingly identified as a key factor in Gulf War Illness, suggesting newfound roles in other diseases. This Continuing Education course will explore the wide roles mitochondria play in response to cellular stress and xenobiotics beyond bioenergetic alterations. It will also seek to challenge how researchers traditionally examine and include mitochondrial toxicology in their work. Speakers with expertise in mechanisms and assessment of mitochondrial toxicity will present (1) an introduction to mitochondrial toxicity, which will focus on the need to examine specific mechanisms of toxicity within mitochondria in order to understand the resultant adverse outcomes; three case studies displaying the methods used and mechanisms of mitochondrial toxicity that extend beyond alterations to bioenergetics including (2) mitochondrial iron homeostasis and its role in acetaminophen hepatotoxicity, (3) antiviral medication-induced alterations to heart epigenetic and metabolic landscapes, and (4) the role of mitochondria in function of the innate immune system and inflammation. Next, we will progress from in-depth mitochondrial mechanisms to how this knowledge can be applied by using (5) mitochondria as biomarkers for renal exposures. Finally, in a world with an ever-expanding need for toxicological assessment of new drugs, toxins, and toxicants, we will explore (6) how mitochondrial testing has been improved and conducted in large Pharma and (7) how large Pharma is upscaling mitochondrial toxicity testing in order to meet increased future demand.

Following the session, attendees will have a clear understanding of the dynamic roles mitochondria play within the cell and at tissue and organismal levels, the challenges and current solutions analysis of mitochondrial endpoints presents, and a new perspective on the role of mitochondria in toxicological mechanisms. Further, they will be empowered to assess how these less understood mitochondrial mechanisms may play key roles in their own work, ultimately expanding and improving toxicological evaluations.

Course Book

Room:
Room 209

Chair(s):
Caren Villano, Boehringer Ingelheim Pharmaceuticals Inc.; and Edward Marsden, Charles River, France.

Traditionally, rats, mice, and rabbits have been used as preferred animal models (rodent and nonrodent) for nonclinical developmental, reproductive, and juvenile toxicity testing. Published regulatory guidelines recommend the selection of relevant animal models—based on individual project requirements—that may be influenced by systemic exposure and prior systemic toxicity data derived from general toxicology studies. Most compounds use traditional models that are quite effective and widely accepted by international health authorities. Species-specific dose-limiting toxicity, differences in metabolism across test species, and pharmacological relevance may require researchers to investigate nontraditional models including guinea pigs, mini-pigs, and dogs. In addition, certain pharmacological classes (e.g., antibiotics in rabbits) or chemistries may also limit the use of traditional models. Further, in the last year, during the COVID-19 pandemic, a severe shortage of nonhuman primates (particularly sexually mature females needed for ePPND studies) shifted the focus toward nontraditional animal models. This CE course will walk participants through the various considerations for study designs as well as the pros and cons of more common nontraditional mammalian models in DART and juvenile toxicity testing. It will also touch upon the use of rabbits and their limitations in fertility and juvenile animal studies.

The first presentation will describe how collaboration between animal model suppliers, industry, and academia has driven scientific development and expanded the use of the Göttingen Minipig into DART and juvenile toxicology, with specific projects highlighted. The second presentation will focus on the use of beagles in developmental and juvenile toxicity testing, including many critical aspects of study design, associated species differences, and terminology. The third presentation will explore the scientific considerations for the selecting of alternatives to nonhuman primates in order to address embryo-fetal risk and provide examples of how transgenic, knockin and knockout animal models and surrogate molecules can be used to support nonclinical hazard assessment for various biotherapeutics. The course will end with a summary of the current regulatory guidance on DART and juvenile animal toxicity testing, which includes discussion of the use of nontraditional species or models. Following this course, participants will be familiar with a variety of approaches to assessing embryo-fetal risk and juvenile toxicity in animal models not commonly used in DART as well as the current regulatory guidance supporting them.

Course Book

Room:
Karl Dean Ballroom C1

Chair(s):
David Reif, North Carolina State University; and Shannon Bell, RTI International.

The rapid expansion of computational and in vitro methods for the analysis of chemical-biological interactions has evoked a wealth of open-source tools and resources that enable discovery and analysis. This supports increased use of these resources in order to aid chemical assessments and support the finding and generating information for prioritization, study waivers, weight of evidence, and other regulatory applications. Many of these new tools are open access and web-based, which enables broader access.

This session will provide attendees with an understanding of open-source and often web-based tools and resources that can be applied in a context-specific manner for understanding chemical-biological interactions and informing chemical assessments. We will open with an overview of regulatory testing strategies that incorporate the use of nonanimal methods in order to provide a background on how these tools and resources can be used. The next three presentations will provide an overview of resources that contain traditional and NAMs testing data as well as tools that support the assessment needs. Case studies will be used as reference points for participants, who can also work through the course material at their leisure. These presentations will address the following: how can we find existing data for a given chemical or chemicals that are structurally similar, how can we determine whether existing data can be used to fill in gaps of information, and how can computational models be leveraged to generate predictions that increase the weight of evidence?

Our final presentation will highlight various new tools and opportunities to derive narratives of chemical-biological interactions. Together these presentations are intended to inform participants on pertinent resources available and provide a practical guide on when and how to use them.

Objectives: Introduce participants to the mechanisms in which nonanimal approaches can be used to support assessments. Highlight resources for access to data and tools that enable the following applications: waivers; read-across; defined approaches and integrated approaches to testing and assessments (IATA); and QSAR-based modeling. Showcase new resources to complement narratives.

Course Book

Room:
Room 202

Chair(s):
Kelly Salinas, SRC Inc.; and Marc Stifelman, US EPA.

Building on courses from previous years, this session seeks to provide members with a brief overview of systematic review (SR) methods and principles, which will be followed by analyses of how these methods can be applied to or interpreted as information beyond traditional human health hazard endpoints (e.g., epidemiology and animal toxicity studies evaluating apical endpoints). SR methods using unbiased, reproducible, transparent approaches have been implemented in order to evaluate data streams. The application to a broader base of evidence is crucial to the practice of risk assessment, given that exposure characterization ecological receptors inform assessment conclusions.

The first talk will provide a brief review of SR principles and be followed by an overview of the translation of principles and techniques of SR across diverse disciplines (i.e., ecotoxicity, environmental fate, exposure, mechanistic, and in vitro/in vivo toxicity testing data). We will then discuss the unique aspects and challenges of applying SR to these disciplines.

The second speaker will discuss how ECOTOXicology Knowledgebase (ECOTOX) literature review and data curation protocols, while ECOTOX-specific, were designed to align with SR methods. Methods were developed to ensure that ecotoxicity data were extracted in sufficient detail in order to support independent evaluation, synthesis, and/or review of ECOTOX data documents ranging from scoping documents to regulatory decision-making.

The focus of the third presentation will be the application of SR methods to environmental fate endpoints, and how the systematic evaluation of these endpoints influences prioritization, assessment, and prediction of human health and ecological hazard and toxicity. The development of a fit-for-purpose evaluation framework to systematically assess data unique to environmental fate endpoints, including field/monitoring data and data estimated from environmental fate and transport models will be described.

The fourth presentation will center on the validation and application of SR methods to environmental exposure data—specifically the data required to estimate daily soil ingestion rates in humans. We will also discuss thee application of SR principles, including the development of a Population, Exposure, Comparator, and Outcome (PECO) statement specific to the soil ingestion of contaminants.

The fifth speaker will consider challenges associated with using SR principles in the synthesis and integration of mechanistic data. Adjustments of SR methods needed to evaluate mechanistic data, including a definition of the objective/scope of the use of the data and selection/refinement of an appropriate critical appraisal tool for various types of mechanistic data (e.g., in silico, in vitro, in vivo, and epidemiological data), will be presented. Case studies will be used to demonstrate that these SR adjustments rely on knowledge of standard constructs and methods used in toxicology and/or risk assessment.

The final speaker will consider evidence-based methods forassessing the correlation of in vitro data (from ToxCast) and in vivo data (from standard toxicity studies and human clinical trials) in order to predict human health hazard. A case study will be presented to show how data from these streams were evaluated systematically in order to predict the effects associated with two antidiabetic drugs in humans.

This CE course will demonstrate how SR methods, which are developed to evaluate human health toxicity studies, are being applied to other data streams. The course will provide attendees with the working knowledge base required to assess diverse endpoints using SR methods. Furthermore, this course will appeal to attendees of diverse backgrounds and toxicological disciplines who are interested in studying and applying SR methods, including scientists developing and conducting studies related to ecotoxicity, environmental fate, exposure, mechanistic in vitro/in vivo toxicity testing, and others), along with risk assessment practitioners and regulators.