Continuing Education

Course Book

Room:
CC Ballroom 6C

Chair(s):
Catherine Willett, Humane Society International; and Paul Russell, Unilever Safety and Environmental Assurance Centre, United Kingdom.

There has been significant progress globally over recent years in advancing the science to underpin nonanimal cosmetic safety assessment. In addition, citizen-led initiatives that prohibit animal testing of cosmetics and cosmetic ingredients are expanding geographically every year. These advances are leading to the need for global capacity building among the regulated and regulatory communities for completely animal-free safety assessment of consumer products. In the European Union, there has been a ban on animal testing of cosmetics since 2004 and a sales ban on cosmetics tested on animals since 2013; nevertheless, because of testing requirements in other sectors or geographies, animal testing of cosmetics continues. To enable confident decision-making regarding the safety of cosmetics and personal care products, it is important to build confidence in the requisite methodologies based on experience. Toward this aim, an in-depth educational program has been developed by the Animal-Free Safety Assessment (AFSA) Collaboration, a partnership of nonprofit organizations and industry. Achieving a confident risk assessment of a consumer product or ingredient without data from new animal testing requires a novel approach to the assessment, as well as integration of several types of in silico and in vitro data. This Continuing Education course will provide a primer on the necessary tools, including understanding the regulatory playing field, risk assessment problem formulation, estimating consumer exposure, in silico and in vitro approaches to filling data gaps, and estimating an in vitro point of departure—plus, a case example demonstrating how to combine all these elements into a well-documented assessment based on the modules developed by the AFSA Collaboration. Each of the presentations, given by a partner representative with the relevant expertise, will include a set of learning objectives to stimulate audience participation; after the presentations and before the open discussion, there will be a short crowdsourced quiz via Slido on the material presented. An open discussion/roundtable will include one to two participants with regulatory experience.

Course Book

Room:
CC Room 7

Chair(s):
Emanuela Corsini, Università degli Studi di Milano, Italy; and Dori R. Germolec, NIEHS.

Over the last several decades, a great deal of progress has been made in the development of alternative methods to assess immunotoxicity, for both inappropriate immunostimulation and immunosuppression. Immunotoxicology hazard identification requires novel approaches and strategies, possibly without the use of animals to be in line with the vision of toxicology in the 21st century. In vitro methods anchored to adverse outcome pathways (AOPs) currently under development or already accepted at the Organisation for Economic Co-operation and Development (OECD) level, associated with identified key characteristics (KCs) of immunotoxicants, and the combination of complementary information, in the context of an Integrated Approaches to Testing and Assessment or a Defined Approach, offer the opportunity to identify the hazard that xenobiotics may pose to the immune system. This Continuing Education course aims to highlight animal-free approaches in immunotoxicology, and participants will learn how to apply these novel strategies to gain an understanding of how and if substances modulate immune processes. The course will present the KCs of immunotoxicants as an approach for hazard identification and will provide examples demonstrating the use of this framework in the characterization of the toxicity of immunotoxic agents. The use of KCs for the design of tests to evaluate the hazards of novel chemicals to complement or replace existing approaches will be emphasized. In the second presentation, the defined approaches for skin sensitization recently adopted at the OECD level will be presented. Defined approaches have been demonstrated to be more reliable and human relevant than stand-alone in vitro tests or the commonly employed in vivo test methods. The third presentation will discuss integrated testing strategies for the identification of xenobiotic-inducing immunosuppression, including high-dimensional profiling pathway analyses and computational approaches to integrating immune-related data and outcomes assessments. Finally, the Universal Immune System Simulator (UISS), a simulation framework to model the immune system, will be introduced. The UISS software is free and has been used for hazard characterization of pharmaceuticals. The application of this software for evaluating environmental contaminants will be demonstrated. The presentation of these novel approaches will enable course participants to gain an understanding of how mechanistic-based testing strategies can be applied to evaluate the adverse effects of chemicals on immunity.

Course Book

Supplement: In-Depth Presentation Slides for Dr. Whaley

Room:
CC Room 1

Chair(s):
Amy Wang, NIEHS/NTP; and Xabier Arzuaga, US EPA.

Besides traditional, narrative reviews, other review types are increasingly being used in toxicology and recognized for their strengths. For instance, systematic review has joined the narrative review on the short list in the hasten publication type filter on PubMed. Systematic reviews, a format originating from the clinical research field, offer balanced answers to predefined questions with transparent steps and comprehensive consideration of diverse, including conflicting, results. They are considered the gold standard in many agencies for hazard identification and/or risk assessment of carcinogenic and noncarcinogenic effects from chemical, physical, and biological agents, mixtures, lifestyles, and other scenarios. Evidence map (survey the available research evidence), scoping review (evidence map with a descriptive narrative summary of the results, typically without data extraction or study quality assessment), rapid systematic review (faster completion than a systematic review with or without review shortcuts), umbrella review, and mixed type of review each can fit different needs while requiring fewer resources than a systematic review. This course is designed for toxicologists at all stages of their careers and will explain the review types, how to know which type is right for your question and situation, how to complete selected types of the review, and how to publish them, including interim products, in peer-reviewed journals. Many early steps in the process are highly similar among these highlighted review types, and participants will be able to build knowledge and know-how by following the presentations in the designed order. At the end of the course, the participants will be able to (1) distinguish different types of reviews; (2) prepare an evidence map, scoping review, rapid systematic review, or systematic review that fits their needs; (3) use computational tools to simplify and fasten the process; and (4) write a competitive manuscript to amplify the impact of their work.

Course Book

Room:
CC Ballroom 6E

Chair(s):
Paul Price, Independent Researcher; and Elke Jensen, Dow Chemical Company.

The fields of exposure science and toxicology are changing, and these changes have the potential to improve our ability to assess risks from concurrent exposures to multiple chemicals. The changes include advances in exposure monitoring; the development of structure-based predictions of chemical properties relevant to exposure assessment and/or relevant PK modeling of internal doses; the development of new approach methodologies (NAMs); advances in modeling variation and uncertainty in exposure and dose-response; and the creation of curated databases of information on toxicity and exposure. This course presents a review of how these advances can, and likely will, change mixture risk assessments. The course will begin with an overview of the existing approaches for mixture risk assessment, the limitations of these approaches, and the identification of the types of information and tools needed to improve the assessments. The remainder of the course will consist of four talks on how changes in scientific disciplines relevant to mixture toxicology, such as cumulative exposure assessment, toxicokintics, toxicodynamics, and data organization, are helping to address the needs of mixture risk assessors. Each of the talks will describe how advances in the field are improving the ability to assess mixture risks (with case studies) and what could be done in the future. The first talk will focus on how advances in exposure science can be used to improve our ability to rapidly characterize multiple chemical exposures in an individual and how these combined exposures vary across individuals. The second talk will address advances in our understanding and ability to model chemical interactions that involve the toxicokinetics of the chemicals. The third talk will discuss the testing of mixtures of chemicals using in vitro assays to characterize interactions of chemicals in terms of common molecular initiating events, key events, and certain apical effects. The final talk will recast our understanding of the mixture risk assessment process using the concepts of the aggregate exposure pathways (AEP), adverse outcome pathways (AOP), and AEP–AOP networks. This talk will include a description of a proposed taxonomy for chemical interactions that can help organize existing data on mixture toxicity. Together, the talks will describe the relevance of scientific advances to the assessment of risks from exposures to multiple chemicals. The course will discuss assessing risks from exposure to discrete mixtures of chemicals and from exposures to multiple sources (cumulative exposures). While many of the issues discussed apply to ecological effects of mixtures, this course will focus on the effects on human health.

Course Book

Room:
CC Room 8

Chair(s):
Christopher Bowman, Pfizer Inc.; and Pragati S. Coder, Charles River Laboratories Ashland LLC.

Age and reproductive status are often overlooked variables in mammalian nonclinical studies, but they can have a significant impact on the evaluation of the reproductive system, the interpretation of potential experimental- or test article–related findings, and ultimately the risk assessment. The reproductive system of male and female test species undergoes considerable changes as it transitions from immature to puberty and into fully sexually mature. The timing of puberty and sexual maturation varies across species and sexes and is a major variable in acute/subchronic and reproductive toxicity testing. In females, there also is an age-associated decline in reproductive performance, termed reproductive senescence. In chronic toxicity testing, the effects of reproductive aging are not likely to be seen in nonrodents (e.g., dogs, nonhuman primates, and minipigs) because of their relatively long life spans; however, this can be a major complicating factor for female rodents. An appreciation and understanding of these developmental and age-related changes in the reproductive system is critical to study design, execution, and interpretation for a variety of in vivo experimental disciplines, including toxicology (general, juvenile, investigative, DART, etc.), mouse models, and discovery efforts. The objectives for this course are to provide attendees with an overview of the basic biology of sexual maturation in males and females and reproductive aging in females and to review the effects on study design, data interpretation, and extrapolation to humans.

This course will complement the Continuinig Education (CE) course “The Male Reproductive Tract: Development, Toxicology, and Pathology,” which was presented as part of the scientific program during the Virtual 2020 SOT Annual Meeting, and the CE course “Development, Toxicology, and Pathology of the Female Reproductive Tract: Interpretation of Findings from the Pathologist and Regulatory Perspectives,” which was presented as part of the scientific program during the Virtual 2021 SOT Annual Meeting. These courses are available as part of SOT CEd-Tox, the Society’s online Continuing Education course program.

Course Book

Room:
CC Ballroom 6B

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

Drug discovery toxicology starts at the very beginning, when a new target is proposed for entry into the portfolio. After confirmation of the target, the discovery toxicologist will serve as an integral member in lead optimization and candidate selection for progression into GLP toxicology studies. A lead candidate is selected through rigorous in silico and in vitro screening and subsequent in vivo pilot toxicology studies that enable a preliminary assessment of safety. In this course, the speakers will provide a comprehensive overview of the target toxicity evaluation, chemical series and compound de-risking strategies, and approaches leading to lead identification and the first in vivo pilot toxicology studies. The identification of any potential liabilities associated with the target and their relevance for the patient population and indication contributes to the decision to invest in the exploration of a particular target. After the decision is made to drug a chosen target, the discovery toxicologist will become a critical member of the early discovery team, where the selection of lead compounds will be discussed to finally enable the identification of a candidate to take into GLP toxicology studies. To select a molecule with a safety profile that provides an optimal chance of clinical success, strategies are developed by selecting a panel of in silico, in vitro, and in vivo experiments. How these in silico and in vitro strategies are developed to provide optimal chemical series and compound de-risking will be discussed. Other presentations will focus on the in vivo experiments where PK/PD modeling and ideally early human dose predictions are needed to drive decisions on dosing frequency and dose selection. Early in vivo pilot toxicology studies will be discussed, with a focus on their design, interpretation, and impact. The course will conclude with an interactive investigative toxicology case study session where different case studies will be discussed with the audience. While this session focuses on strategies for small molecules, the overall concepts, approaches, and technologies are generally informative for biotherapeutics and new chemical modalities.