Continuing Education

Course Book

Room:
Room 251 D, Salt Palace Convention Center

Chair(s):
John Norman, American Chemistry Council; and Todd Gouin, TG Environmental Research, United Kingdom.

Microplastics, once relatively unknown, have become the focus of local, national, and global interest. Microplastic particles are one subset of plastic debris primarily characterized as having a size of less than five millimeters down to one micrometer; plastic particles smaller than this size are typically termed nanoplastic particles. Together, these particles also may be called NMPs for short (nano- and microplastics). Microplastic particles can either result from the discharge of plastic materials originally manufactured at that size (primary microplastics) or from the degradation of larger plastic debris (secondary microplastics). However, before researchers begin to tackle the question about microplastic risk, you must understand how plastic is manufactured.

Plastic begins as polymers, and through the application of energy (e.g., heat) and incorporation of the desired additives, a plastic material is created. Additives are chemicals intentionally added to plastics to provide a function fit for the purpose to provide, improve, modify, or retain plastic properties such as preventing fire and providing flexibility, durability, or stability during the plastic lifecycle. Additives often are included in plastics because without additives, the plastic materials would have limited applications, be brittle, potentially degrade, and have a very limited shelf life. It is this combination of particle characteristics (e.g., size, shape, polymer type) and the presence of chemical additives that presents toxicologists with a sizable issue.

Another challenge to understand the potential risks of microplastics is the number of potential chemistries used as additives. There is a vast amount of information available through existing regulatory programs; programs like the US Food and Drug Administration’s food contact notification and the Threshold of Toxicological Concern model, coupled with the European Chemicals Agency REACH registration, are sources of valuable exposure and toxicological information. If there is no exposure and toxicological data, scientists can turn to frameworks to predict potential exposures and risks. To reduce the complexity of the issue, scientists might look at human exposure to screen out chemical additives that are low risk due to low exposure potential.

In this course, the first presenter will focus on modeling probabilistic estimates of both direct exposure (e.g., food packaging) and exposure from modifications to an existing numerical bioaccumulation food web model. The second presenter will discuss how risk can be estimated with a newly developed framework when traditional exposure and toxicity data have not been developed, but the molecular structure and chemical tonnage of a chemical is known. These presentations will provide attendees with a new perspective on critical issues toxicologists face studying microplastics and their potential effects on human health.

Course Book

Room:
Grand Ballroom J, Salt Palace Convention Center

Chair(s):
Koren Mann, McGill University; and Johnny Wise, University of Louisville.

Of the 118 elements in the Periodic Table, 95 elements are classified as metals, and 34 of these have been identified to be hazardous to human health. Differing from organic chemicals, metals’ chemical forms may change, but their basic unit is neither created nor destroyed. Thus, a persistent distribution of metals in the ecosystem with no environmental half-life renders the body system susceptible to metal toxicity in every stage of human life. Exposure to metals occurs in daily life through one’s lifestyle, food intake, occupation, or medical treatment. Considering a worldwide growing geriatric population, the possibility of metal exposure in accelerating the aging process has drawn public attention. For the past half century, assessment of total body metal burden and metal toxicity depends largely on conventional techniques such as atomic absorption spectrophotometry and bioassays; however, more recently, real-time analyses and molecular approaches for gene-environment interactions have been implemented. This advanced course invites experts to address interconnected subjects in metal toxicology.

After a general introduction to metals, the first lecture introduces recently developed innovative technologies to determine level of exposure, such as x-ray fluorescence and neutron activation analysis for real-time, noninvasive, nondestructive quantitation of metal levels in bone, nail, hair, and other tissues. The second lecture discusses recent advancements in ’omics-based technologies, such as whole genome and CRISPR-based screens, in understanding the genetic susceptibility that contributes to metal toxicities. The third lecture uses the body as a whole system to address metal toxicity in an aging population from the impact of aging itself on metal toxicity to the impact of metals on aging. The last lecture further discusses the role of the US Food and Drug Administration in the regulation and safety assessment of metals in food additives. Throughout the course, concerns related to human exposure to these metals and potential risk will be raised and discussed with particular emphasis on metals of concern, such as lead, arsenic, manganese, and mercury.

The course serves well for those who desire an advanced knowledge on metal toxicity in lifespan, metal-gene interaction, risk assessment/regulation, and advanced technical approach for metal quantification. The course will be of interest to those engaged in wider aspects of metal toxicology, mechanism of chemical toxicity, neurotoxicology, carcinogenesis, risk assessment, regulatory and safety evaluation, and occupational and public health.

Course Book

Room:
Room 250 D, Salt Palace Convention Center

Chair(s):
Sarah Campion, Pfizer Inc.; and Jessica LaRocca, Corteva Agriscience.

During the pre-implantation period, there are major developmental events that occur, and knowledge of these events is critical for understanding and interpreting potential effects on fertility and early embryonic development. Embryo-fetal development is a complex process that initiates following implantation. The development of the major organ systems during gestation varies in timing across species and drives the design of nonclinical studies conducted to assess the potential human risks of drugs or chemicals. This course will focus on the basic biology of implantation, early embryonic development, and organogenesis, while discussing comparative cross-species timelines and critical periods during development.

In addition to reviewing the key developmental processes and events that occur during the pre-implantation and post-implantation periods, the first two speakers will provide examples of phenotypes that arise following exposures to chemicals or drugs during sensitive developmental periods. The information presented will provide attendees with a basis for interpreting the potential mode of action, as well as interspecies comparison to aid in human risk assessment.

After this critical background information that is the biological basis for prenatal developmental toxicity testing, the succeeding presentations will discuss the design of nonclinical developmental toxicity studies for agrochemicals and pharmaceuticals. These speakers also will present key information on how study outcomes are interpreted and impact human risk assessment. Specific case studies and mode-of-action studies for determining human relevance will provide attendees with real-world examples of how to apply the information presented in this course. Novel approaches for developmental toxicity testing, including the use of comprehensive toxicogenomics data and the use of alternative assays as outlined in ICH S5(R3), also will be discussed, with the aim of providing attendees with a perspective on the evolving future of developmental toxicity testing.

Course Book

Room:
Room 251 A, Salt Palace Convention Center

Chair(s):
John F. Wambaugh, US EPA; and Barbara A. Wetmore, US EPA.

Next-Generation chemical risk assessment (NGRA) aims to replace and expand traditional toxicity testing via new approach methodologies (NAMs) including in vitro screening. Translating in vitro points of departure (PODs) to in vivo contexts requires in vitro–in vivo extrapolation (IVIVE) based on toxicokinetics. IVIVE methods for single chemicals were developed and vetted by the pharmaceutical industry. However, NGRA is intended to accelerate the pace of chemical risk assessment, potentially generating in vitro PODs for thousands of chemicals and endpoints. These data require chemical-specific IVIVE to be interpreted as in vivo PODs. To allow higher-throughput IVIVE, higher-throughput toxicokinetic (HTTK) methods are needed. Public health risk chemical prioritization efforts based on HTTK are under consideration at the US Environmental Protection Agency, Health Canada, and the European Food Safety Authority.

This course, which focuses on high-throughput approaches for translating NAMs into PODs, complements but is distinct from fellow 2024 SOT Continuing Education (CE) course “Putting Theory into Practice: Using Computational New Approach Methodologies in Next-Generation Risk Assessment,” which focuses on integrating all NAMs needed for next-generation chemical risk assessment. Further, with its focus on high-throughput IVIVE, it is distinct from previous years’ CE course offerings focused on other aspects of physiologically based kinetic modeling and toxicokinetics.

HTTK is playing an increasing role in creating more predictive toxicological methods by allowing (1) conversion of external dose metrics (such as mg/kg/day) to internal/tissue dose metrics and (2) relating in vitro PODs to human-relevant doses. With confirmed speakers that include subject matter experts with many years of experience in the development and application of these tools, this course aims to (1) educate researchers to use high-throughput IVIVE to estimate toxicological PODs in their work and (2) allow decision-makers considering the use of NAM-based PODs to be better informed about the capabilities and limitations of high-throughput IVIVE. Attendees of this course will become familiar with the types of data, models, and tools needed to create “bioactivity:exposure ratio” risk-based prioritizations, and other rapid IVIVE techniques. These tools will include SimCyp, httk, and WebICE. While single chemical IVIVE has built a strong foundation, this course will focus on IVIVE to inform models of toxicity that can be applied to large numbers of chemicals. Each of the four main presentations will provide examples that can be easily adapted to the attendees’ research questions and risk assessments.

Course Book

Room:
Room 250 A, Salt Palace Convention Center

Chair(s):
Eryn Slankster-Schmierer, Physicians Committee for Responsible Medicine; and Elizabeth Baker, Physicians Committee for Responsible Medicine.

The acute toxicity of chemicals, mixtures, and formulations has traditionally been assessed with an animal-intensive in vivo battery of tests that in the context of pesticides is collectively referred to as the “six pack.” These tests include methods to address acute oral, dermal, and inhalation toxicity; primary eye irritation; and dermal irritation and sensitization. In light of recent retrospective reviews of in vivo test method performance, the ability of the individual components of the test battery to reliably predict human-relevant responses to chemicals has been in question. In recent years, international collaborations have led to partial and full replacements for several of these endpoints.

In this course, attendees will receive an overview of ongoing efforts and an up-to-date strategy to implement reduction and replacement of animals used for acute toxicity in health hazard and risk assessment of chemicals and end-user product formulations for chemical markets, including drugs, pesticides, and consumer products. The first portion of the course will provide strategies for predicting, waiving, and measuring oral, dermal, and inhalation lethal doses in order to minimize animal use. LD50 tests have been used for nearly a century and still guide regulatory decision-making, with acute oral lethal dose studies the most prevalent, despite poor reproducibility for Globally Harmonized System of Classification and Labelling of Chemicals categorization. The first talk will cover computational approaches to predict acute oral toxicity using the OPERA suite, a free and open-source/open-data suite of QSAR models providing predictions on physicochemical properties, environmental fate, and toxicity endpoints. The second speaker will outline strategies for waiving in vivo acute dermal toxicity tests for US Environmental Protection Agency requirements, including the implementation of bridging principles to leverage data already gathered and reduce additional testing. The third talk will cover human-relevant approaches to overcome the anatomical and physiological respiratory differences that make rodents poor predictors for human inhalation toxicity. The second portion of the course will cover advanced in silico, in vitro, and ex vivo methods for non-lethal acute endpoint studies. The fourth speaker will cover in vitro methods showing improved reliability and human-relevance relative to the Draize test, as well as proposed avenues for the development of a defined approach for dermal irritation. The fifth speaker will cover the methods in the defined approaches for serious eye damage and irritation, offering a full replacement for the Draize eye test in rabbits. Finally, the last talk will round out the six-pack assessment by covering methods within and updates to the defined approach to skin sensitization, including presenting information on the first fully nonanimal defined approach as an effective replacement for the mouse Local Lymph Node Assay and guinea pig maximization tests for dermal sensitization.

In sum, this course will prepare agency and commercial risk and hazard assessment attendees to replace and reduce animal use in acute toxicity testing batteries wherever possible by offering up-to-date guidance on modern nonanimal methods.

Course Book

Room:
Grand Ballroom F, Salt Palace Convention Center

Chair(s):
Ashwini Phadnis Moghe, Takeda Pharmaceutical Company Limited; and Shermaine Mitchell-Ryan, HESI.

Cell and gene therapies have emerged as an exciting breakthrough treatment for liquid and solid tumors in regenerative medicine and for the treatment of rare monogenic disorders as well as a wide range of acquired diseases with limited therapeutic options. While these therapies hold tremendous promise in treating complex diseases, they can be associated with significant immune safety concerns that should be carefully considered during preclinical and clinical development. Such risks may include off-target toxicities, integration-associated genomic toxicities, mutagenic transformation, organ/tissue damage, immunogenicity, and exaggerated activation of the immune system. These therapies also are accompanied by a unique set of challenges where standard safety assessments may not apply and additional testing is warranted, often involving novel de-risking approaches and post-marketing surveillance depending on the therapy in question. Recent advances in the field, along with the sustained momentum in developing safer and more effective next-generation cell and gene therapies, have encouraged a closer examination of the promise and the pitfalls associated with this rapidly evolving class of therapies.

In the first talk of this course, attendees will be guided through the history of these advanced therapies, dating back to the first human gene and cell therapies to the present day approved therapies, along with a description of current nonclinical and clinical strategies designed to overcome hurdles associated with immune-related events. Then, the course will take a deeper dive into immune system considerations for cell and gene therapies with the second talk focusing on the immune barriers to in vivo gene therapies, such as immunogenicity to viral and nonviral (i.e., liposomes, nanoparticles) therapies. This talk also will provide pointers to toxicologists for assessing immunotoxicity issues in gene therapy. The third talk will focus on operational aspects of immune system monitoring during the conduct of a nonclinical study from the contract research organization perspective. The fourth speaker will focus on nonclinical safety assessment for engineered CAR-T therapies, with a focus on immunosafety risks posed by engineered Teff and Treg cells, paving the way for the fifth speaker to discuss the next generation of cellular and gene therapies, including an overview of gene editing to avoid graft vs. host disease.

Course Book

Room:
Room 251 D, Salt Palace Convention Center

Chair(s):
Anna Lowit, US EPA; and Gina Hilton, PETA Science Consortium International.

The depth and breadth of information used to characterize hazard and exposure have expanded beyond traditional in vivo studies to encompass ’omics, in vitro, and computational approaches. Interpreting various lines of scientific evidence is rarely unambiguous or straightforward, as the same information can support multiple legitimate interpretations and conclusions. The weight of evidence (WOE) approach is, therefore, essential in toxicology and risk assessment to support decision-making. Although some tools are available to enhance transparency and consistency in WOE, professional judgement remains necessary in almost all cases to evaluate the strengths and limitations of each data source. Subject experts also are expected to provide knowledge-based insights on how various factors, such as experimental design, can influence data comparability. WOE is particularly challenging due to the diverse regulatory and scientific contexts involved in the analysis. Therefore, WOE must be fit for purpose and framed in problem formulation. This course will provide attendees with an understanding of the underlying concepts, principles, and techniques of WOE analysis in the context of chemical risk assessment.

Since the WOE approach is flexible and adaptable (i.e., it can be tailored to fit specific risk assessment contexts or regulatory requirements), this course will use case examples to demonstrate the integration of various lines of scientific evidence generated from both conventional and new approach methods for different purposes, including industrial chemicals, personal care, fragrance, and agrochemical sectors. The case examples will illustrate the concept of fitting WOE to a specific purpose, including optimizing the design of animal toxicity studies (where required), estimating points of departure using nonanimal data, and predicting toxicity of a structurally similar chemical with limited or no toxicity data, as well as merging monitoring data and exposure model predictions.

The introduction will describe the overarching, flexible, and adaptable principles in WOE and problem formulation that will be illustrated throughout the course. The first presentation will cover the fundamental principles in problem formulation, including defining resources and contexts, and computational tools to integrate and evaluate data for fit-for-purpose WOE. A WOE approach using multiple lines of evidence for contemporary study design for regulatory required animal studies to maximize the use of computational modeling, in vitro, and pharmacokinetic data will be shared in the second talk, while the third presenter will discuss a WOE approach for considering the appropriateness of new in vitro inhalation methods for the evaluation of fragrances in risk assessment. The fourth presentation will focus on interpreting multiple lines of evidence using in vitro and computational approaches for safety evaluation of cosmetics. The next presenter will show WOE across in vitro physiologically based kinetic and short-term in vivo data to consider human relevance of particular hazards. The course’s final presentation will focus on exposure assessment and a WOE approach for evaluating and applying measurements and models together in exposure characterization, followed by an interactive session where each presenter will pose a question to test attendee knowledge of fit-for-purpose WOE and problem formulation principles and application.

The learning goals for this course are to (1) understand the value and content of problem formulation; (2) gain knowledge in the concept of fit-for-purpose WOE and its connection to problem formulation; (3) learn how WOE analysis can be used to analyze data and evaluate risks for chemicals that have varying degrees and types of available data; and (4) learn about different types of risk assessments and decision contexts.