Continuing Education Courses

Continuing Education courses will be held October 25th, from 9:00 - 11:00 am. Courses are free but advanced registration is required. If you have already registered for the meeting but did not select a course and wish to attend, email the meeting organizers at [email protected] by the advanced registration deadline of September 15th.

See below for details of each course.

CE 1 | CE 2 | CE 3 | CE 4

CE 1: Guidance for the application of New Approach Methods (NAMs) for hazard and risk-based estimates using the Exposure And Safety Estimation (EAS-E) Suite platform

Alessandro Sangion1, James Armitage2, Li Li3, Jessica Ponder4Jon Arnot1,5

1ARC Arnot Research and Consulting, Toronto, Canada. 2AES Armitage Environmental Sciences, Ottawa, Canada. 3University of Nevada Reno, Reno, USA. 4Physicians Committee for Responsible Medicine, Washington, USA. 5University of Toronto, Toronto, Canada

 

New Approach Methods (NAMs) such as in vitro bioactivity assays are being developed to advance the capacity and pace of chemical assessment. Knowledge of chemical distribution in the test system is important to confidently apply the results for hazard and risk assessment. In Vitro Mass Balance Models (IV-MBM) provide quantitative predictions for chemical distribution in the bioassays and determine if significant volatilization, binding, or saturation has occurred. To apply the in vitro data in a risk-based context, in vitro-in vivo extrapolation (IVIVE) models that include toxicokinetic (TK) models, and related model input parameters are required. Aggregate exposure models for humans and ecological receptors, e.g., PROduction-To-EXposure High-Throughput (PROTEX-HT), can also be applied to estimate exposures. Combined these NAMs and models can estimate potential risk and help experimental design, i.e., dosing values. This Continuing Education describes a workflow to estimate Administered Equivalent Doses (AEDs) from nominal in vitro medium concentrations and steady-state blood concentrations (CSS) using the IV-MBM and IVIVE models and then to compare these values with exposure predictions to calculate bioactivity-exposure ratios (BERs). The workflow is implemented in the free and publicly available Exposure And Safety Estimation (EAS-E) Suite online platform (www.eas-e-suite.com). The EAS-E Suite platform further facilitates the comparisons of different models and assumptions for calculating AEDs and BERs as illustrated for a set of case study chemicals spanning a wide range of partitioning properties and susceptibility to degradation. Recommendations for addressing key data gaps (uncertainties) and increasing confidence in the application of NAMs for regulatory decision-making are discussed.

 

First Presentation: Introduction and orientation to the Exposure And Safety Estimation (EAS-E) Suite platform.

 

Presenter: Jon Arnot

Abstract: Chemicals require safety and risk assessment and the necessary information is quite limited or non-existent for most chemicals. The freely accessible on-line Exposure And Safety Estimation (EAS-E) Suite platform (www.eas-e-suite.com) comprises curated databases of measured physical-chemical properties, environmental degradation half-lives, in vitro and in vivo toxicokinetic parameters, and production volumes for thousands of organic chemicals, as well as quantitative structure-activity relationships (QSARs) for predicting chemical information, if measured data are unavailable. EAS-E Suite includes various multi-media mass-balance (mechanistic) models for environmental fate (indoor and outdoor), in vitro and in vivo toxicokinetics, and exposure models for humans and a range of ecological receptors (plants, invertebrates, fish, birds, and mammals). EAS-E Suite autoparameterizes the built-in models requiring a Chemical Abstract Service (CAS) number, name, or Simplified Molecular Input Line Entry System (SMILES) code for existing chemicals and a SMILES code for new chemicals. An overview of EAS-E Suite is presented.

 

Second Presentation: Estimating steady-state blood concentrations (CSS) and Administered Equivalent Doses (AEDs) from cellular (in vitro) bioassays.

Presenter: Alessandro Sangion

Abstract: In vitro bioassays are being developed to advance the capacity and pace of chemical assessment. Knowledge of chemical distribution in in vitro test systems is imperative to confidently apply the results for hazard and risk assessment. In Vitro Mass Balance Models (IV-MBM) provide mechanistic insights and calculations for chemical distribution in in vitro bioassays and can indicate if significant volatilization, binding, or saturation is expected occurred to aid experimental design and data interpretation. IV-MBM, in vitro-in vivo extrapolation (IVIVE) models, and related model input parameters are required to apply the in vitro data in a risk-based context. This presentation includes an introduction to in vitro toxicokinetic and IVIVE modelling. A workflow to estimate steady-state blood concentrations (CSS) and Administered Equivalent Doses (AEDs) from nominal in vitro medium concentrations using data and models built into the EAS-E Suite platform (www.eas-e-suite.com) is described and applied with a case example.

 

Third Presentation: Exposure predictions and calculating bioactivity-exposure ratios (BERs).

Presenter: Jon Arnot

Abstract: Exposure data are required for risk-based chemical evaluations; however, there is a paucity of relevant exposure measurements. Exposure models are necessary to address data gaps and integrate any available relevant measured information. The PROduction-To-EXposure High-Throughput (PROTEX-HT) model calculates external and internal aggregate chemical exposure to humans and a diverse range of agricultural and ecological receptors requiring only three model input parameters for data poor chemicals: SMILES notation (structure), production volume, and functional use category. PROTEX-HT consolidates data, models, and tools for simulating chemical emissions throughout their lifecycle, chemical fate in natural environments and food webs, chemical fate in indoor environments from use indoors and applications directly to the body, and toxicokinetic models. PROTEX-HT is implemented in EAS-E Suite. This presentation describes the PROTEX-HT model, its evaluation, and combines exposure predictions and in vitro data from Section 2 to calculate bioactivity-exposure ratios (BERs) as a case example.

 

Fourth Presentation: EAS-E Suite demonstration and participant trials

Presenters: Dr. Jon Arnot and Dr. Alessandro Sangion

The instructors will provide specific case example demonstrations of the EAS-E Suite platform and participants will have the opportunity to try EAS-E Suite themselves. If participants are interested in trying EAS-E Suite during the course, it is recommended they bring a laptop or tablet. They can register on-line before or during the course to gain access to the EAS-E Suite platform at www.eas-e-suite.com.

 

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CE 2: Open-access Data and Computational Tools to Investigate Chemical Bioactivity

Aswani UnnikrishnanVictoria HullAlexandre BorrelKim T To, James T Auman

Inotiv, Research Triangle Park, USA

To provide user-friendly access to high quality data and computational tools aimed at providing data from new approach methodologies (NAMs), the National Toxicology Program’s Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) has developed the Integrated Chemical Environment (ICE) and other tools to support chemical safety assessment.  This CE session will introduce the suite of tools included within ICE and three stand-alone tools, ChemMaps.com, the OPEn structure–activity/property Relationship App (OPERA) and the Defined Approaches for Skin Sensitization (DASS) App.  Attendees will gain familiarity with how to search for and interpret data within the ICE platform, and the different ways to retrieve data for chemicals within the ICE database.  This will be followed by a demonstration of multiple interoperable ICE tools that can be used to interactively explore and interpret ICE data, with examples of exploring high-throughput sequencing assays, predicted tissue concentrations, and exposure scenarios.   Attendees will learn to characterize and explore known and unknown chemicals by implementing OPERA models and interactively navigating chemical space with ChemMaps.com. The session concludes with a demonstration of the DASS App for predicting chemical hazard and potency using defined approaches for skin sensitization that have been internationally accepted by regulatory agencies.  By the end of this CE session, attendees will understand how to use the capabilities available within NICEATM’s computational platforms and tools, through demonstrations of tool functionality and applicability using cases studies to characterize chemical use, analyze available data, and identify potential hazards for their chemicals of interest.


First Presentation: Overview of NICEATM’s Integrated Chemical Environment (ICE) with detailed insight into its Search and structural similarity prediction tools

Presenter: Aswani Unnikrishnan

Abstract: The Integrated Chemical Environment (ICE) provides highly curated toxicologically relevant data and analytical tools for data interpretation and exploration. ICE’s Search tool lets users query data for lists of chemicals and mixtures, yielding summary-level information and assay results mapped to mechanistic targets and modes of action. The latest ICE release introduced a beta Search query summary that provides summary visualizations to help users contextualize and interactively explore data.  The Chemical Quest tool enables users to query chemicals or SMILES structures to identify structurally similar chemicals. Query results are ranked based on the similarity of the query chemical fingerprints with chemicals in the ICE database. This presentation will provide an overview of ICE and demonstrate the use of Search and Chemical Quest tools through examples of chemical evaluation use cases, such as identifying information for data-poor chemicals and comparing the bioactivity of chemicals across multiple toxicity endpoints of regulatory concern.


Second Presentation: Using the Integrated Chemical Environment (ICE) to access interoperable computational tools and inform chemical hazard

Presenter: Victoria Hull

Abstract: The interactive, interoperable tools in ICE enable users to interpret large amounts of toxicologically relevant data and implement complex models through a user-friendly interface. Within the Curve Surfer tool, users can visualize concentration-response curves from curated high-throughput screening data. They can also filter on criteria like mode of action, mechanistic target, and bioactivity, narrowing results to those that are most biologically relevant. The Physiologically-based Pharmacokinetic (PBPK) and In Vitro to In Vivo Extrapolation (IVIVE) tools implement models from the EPA’s httk package to estimate chemical tissue concentrations over time and relate in vitro assay measurements to in vivo exposures, respectively. The Chemical Characterization tool can be used to explore physicochemical properties and compare potential chemical use cases through which consumers may be exposed.  We will build upon case studies from the first presentation to demonstrate the use of these tools for exploring data and understanding potential chemical hazards.

 

Third Presentation: ChemMaps.com and OPERA: cheminformatics tools to navigating chemical space and characterize chemicals 

Presenter: Alexandre Borrel

Abstract: With the increasing size and diversity of publicly accessible databases, particularly for environmental chemicals, navigating the chemical space has become crucial. To address this need, we have developed ChemMaps.com, a user-friendly web server inspired by Google Maps. ChemMaps.com facilitates easy exploration of the chemical space by employing complex projection techniques and molecular descriptors. In this new release, we have included all assay results available from the inter-agency ToxCast/Tox21 program. This presentation will demonstrate how ChemMaps.com can be utilized for read-across analysis, risk assessment, and the exploration of unknown chemicals. Additionally, we will introduce OPERA, an open-source suite of QSAR models that provides predictions for chemical properties of environmental significance. OPERA predictions can be downloaded from ICE and ChemMaps.com and can be generated for any new chemicals using the standalone version. 


ChemMaps.com: https://sandbox.ntp.niehs.nih.gov/chemmaps/ 
OPERA: https://ntp.niehs.nih.gov/whatwestudy/niceatm/comptox/ct-opera/opera

 

Fourth Presentation: DASS App: A Web Application for Applying Defined Approaches for Skin Sensitization to Predict Hazard and Potency Categorization 

Presenter: Kim T. To

Abstract: Skin sensitization is a critical regulatory toxicity endpoint associated with allergic contact dermatitis. Defined approaches for skin sensitization (DASS) have been developed to identify potential skin sensitizers by integrating non-animal test methods that represent key events in the skin sensitization adverse outcome pathway. We developed the DASS App, an open-source web application, to facilitate user application of four defined approaches that have been accepted by the OECD or U.S. Environmental Protection Agency. The DASS App enables users to implement non-animal approaches to evaluate chemical skin sensitization without the need for additional software or computational expertise. The app supports upload and analysis of user-provided data, includes steps to identify inconsistencies and formatting issues, and provides hazard predictions in a downloadable format. The DASS App is available on the National Toxicology Program website at https://ntp.niehs.nih.gov/go/40498. 

This presentation will provide background information about the DAs, followed by a demo of the web application.


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CE 3: Putting theory into practice: Using in vitro and computational new approach methodologies (NAMs) in human-relevant risk assessment

Nicole Kleinstreuer1John Wambaugh2Joshua Harrill2Predrag Kukic3

1NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), NIEHS, Raleigh-Durham-Chapel Hill Area, USA. 2US Environmental Protection Agency, Chapel Hill, USA. 3Unilever, Bedford, United Kingdom

 

New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing. The application of NAMs in risk assessment has gained much traction recently, and concrete examples of how to analyze, integrate and interpret NAMs to inform a human-relevant safety decision are beginning to appear in the literature, helping to increase the accessibility of the overall approach. However, as with any novel technology, the use, and data interpretation of NAMs might appear unfamiliar and complicated to non-specialists or novel users, limiting the extent to which industry and regulatory risk assessors can apply them with confidence. The aim of this continuing education course is to bring to life the use and application of NAMs in safety decision-making. The course is aimed to be accessible to the general ASCCT audience, and therefore no prior knowledge is required. The first session will focus on the current regulatory requirements for using NAMs and ongoing activities related to regulatory acceptance. The second and third session will give an overview of a range of NAMs that have already found their application in the exposure assessment, such as physiologically-based kinetic modelling, and in the bioactivity characterization, such as high throughput transcriptomics, high throughput phenotypic profiling, and safety pharmacology assays. In the final session, an example of an industry application of NAMs in safety decision making with regards to systemic toxicity in adults of benzophenone-4 as an ingredient in a sunscreen product will be illustrated.

 

First Presentation: Building Confidence in New Approach Methodologies (NAMs)

Presenter: Nicole Kleinstreuer

Abstract: A transformation in toxicological testing and regulatory decision making has been underway for several decades, embodied by a shift from an exclusive reliance on in vivo animal models to development and implementation of NAMs that may provide more rapid, efficient, and human-relevant information across a broad range of chemicals and endpoints. Evolving considerations around validation of NAMs have led to an increased emphasis on more flexible, fit-for-purpose approaches that consider regulatory needs and are tailored for particular contexts of use. This presentation will discuss current projects and future directions in building confidence in NAMs for safety decision-making, and how such efforts rely upon coordination across international partners and diverse stakeholders. Participants will learn about the regulatory perspective on validation and qualification of NAMs and be provided with examples of applying each essential element of a scientific confidence framework that has been agreed upon by multiple US federal agencies.

Second Presentation: Use of New Approach Methodologies (NAMs) in Human Exposure Modeling

Presenter: John Wambaugh

Abstract: NAMs can estimate points of departure (PODs) in vitro using bioactivity as a surrogate for in vivo hazard data. NAMs for exposure provide the context needed to understand in vitro PODs in terms of public health risk. In vitro-in vivoextrapolation (IVIVE) of PODs requires chemical-specific information on in vitro distribution and in vivo toxicokinetics (that is, absorption, distribution, metabolism, and excretion). Since most chemicals lack data, we use high throughput toxicokinetics (HTTK). HTTK is the combination of in vitro measurement of key determinants of toxicokinetics with generic toxicokinetic mathematical models. NAM-based PODs can then be compared with high throughput estimates of chemical intake to develop tentative bioactivity:exposure ratios. Participants will become familiar with key human exposure modeling approaches and the Systematic Empirical Evaluation of Models high throughput framework that uses Bayesian methods to incorporate multiple exposure models into consensus predictions.

Third Presentation: Use of New Approach Methodologies (NAMs) in Bioactivity Characterization

Presenter: Joshua Harrill

Abstract: This presentation will provide an overview of several types of in vitro NAMs that are being used for chemical bioactivity screening and in vitro hazard evaluation. Technologies discussed will include targeted in vitro NAMs such as a safety pharmacology and cell stress assay panels, targeted phenotypic assays as well as non-targeted high-throughput transcriptomic and phenotypic profiling assays. Examples will be provided explaining how information from these NAMs could be incorporated into fit-for-purpose risk assessment applications such as molecular point-of-departure determination and chemical grouping. Participants will also gain a more thorough understanding of how information from multiple in vitro screening NAMs can be integrated to inform chemical risk assessment.

 

Fourth Presentation: An Example of Application of New Approach Methodologies (NAMs) to Evaluate Systemic Safety for Consumers using Benzophenone-4 as a UV-filter in a Sunscreen Product

Presenter: Predrag Kukic

Abstract: In the final session, participants will learn a way to integrate the presented NAMs using a real case industry application to inform a human-relevant safety decision, judging uncertainty, weight-of-evidence, and regulatory context considerations. In particular, we will illustrate how ab initio safety evaluation could be done for a single cosmetic ingredient. NAM data for Benzophenone-4 used at 5% in a sunscreen body lotion product have been generated and the results will be presented with the purpose of deriving  i) a predicted consumer systemic exposure concentration (SEC) of Benzophenone-4, to compare with ii) point(s) of departure using human-relevant NAMs (PODNAM) which provide information on bioactivity of Benzophenone-4. A Bioactivity:Exposure Ratio (BER) was calculated as PODNAM/SEC, and a decision to whether the BERs provide an adequate basis for safety assurance in the context of the ingredient use scenario will be explained. 

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CE 4: Use of NAMs to Predict EC3 Values for Application in Skin Sensitization Risk Assessment

Argel Islas-Robles1John Yin2Andrew J Keebaugh3

1Institute for In vitro Sciences Inc., Gaithersburg, USA. 2OPI, Wella Company, Calabasas, USA. 3UES, Inc. and Air Force Research Laboratory, Wright Patterson Air Force Base, USA

A skin sensitizer is a chemical which leads to an inflammatory reaction (allergic contact dermatitis) through repeated exposure. Identification of sensitizers has become of prominent importance due to the increased understanding of the many chemicals that humans interact with on a daily basis. Therefore, characterizing the hazard and health risk of sensitizers is needed. Historically, animal models have been used to characterize sensitizers, such as the mouse local lymph node assay (LLNA). Based on to the need to use human-relevant models and due to ethical concerns, new approach methodologies (NAMs) have been developed to assess this endpoint. These include a combination of in silicoin chemico, and in vitro methods which are used in a tiered approach. Various NAMs have been validated, adopted by the OECD, and recognized by regulatory agencies worldwide. More recently, NAM-based data have been leveraged to derive a point of departure for next-generation risk assessment. One promising approach is the prediction of LLNA EC3 values (dose leading to stimulation index of 3.0; considered threshold for positive sensitization) using linear regression models based on data from OECD-validated methods (k-DPRA, Keratinosens and/or h-CLAT). For this continuing education course, participants will learn the key steps to establishing predicted EC3 from NAM-based data with a focus on special cases, and will understand their application in risk assessment via presentations of real life examples and a round table discussion which overall will contribute to expand the applicability of the established method beyond the cosmetic and consumer product ingredients.

First Presentation: Overview of NAMs & Regression Models to Derive Predicted EC3

Presenter: Argel Islas-Robles

Abstract: Historically, animal models have been considered the gold standard to assess the human risk to skin sensitizers. More recently, models that do not use animals, or new approach methodologies (NAMs), have been developed and their use is gaining acceptance for hazard identification. In 2022 Natsch & Gerberick developed a method based on NAMs' data and linear regression models to calculate a point of departure for application in risk assessment in the form of predicted LLNA EC3 values (pEC3). This method allows the establishment of continuous potency data with results obtained from the OECD-validated methods: kinetic direct peptide reactivity assay (k-DPRA), the KeratinoSens™ (KS) assay, and/or the human cell line activation test (h-CLAT). This presentation will include an overview of the NAMs, OECD defined approaches for skin sensitization, the regression models, and how to use these for the generation of pEC3 with a focus on special cases.

 

Second Presentation: Prediction of EC3 Values for Nail and Hair Cosmetic Ingredients Using In Vitro Test Data for Quantitative Risk Assessment

Presenter: John Yin

Abstract: Over the past two decades, there has been an increasing trend towards assessing cosmetic ingredients and finished products using in vitro data. Recently, several linear regression models have been developed that allow prediction of EC3 as from LLNA as point of departure. In this study, nail and hair care ingredients were tested in k-DPRA, Keratinosens assay, and h-CLAT and their EC3 values were predicted with the linear regression models. The predicted EC3 values were then compared with the historical LLNA EC3 data. There was a strong positive linear relationship between the predicted EC3 values and historical LLNA EC3 data. The results of this study support the use of the linear regression models and the in vitro data to predict EC3 values for quantitative risk assessment. The results also demonstrate the flexibility of using a cell-based assay in place of k-DPRA when data of the latter are not available.

 

Third Presentation: Development of Preliminary Candidate Surface Guidelines for Air Force-relevant Dermal Sensitizers using New Approach Methodologies

Presenter: Andrew Keebaugh

Abstract: This study aimed to better characterize the potential link between allergic contact dermatitis (ACD) and chemical exposures during AF operations by 1) evaluating the sensitization potential of AF-relevant chemicals using new approach methodologies (NAMs), and 2) developing preliminary candidate surface guidelines (PCSGs, i.e., guidelines for maximum surface concentrations to prevent induction of sensitization) using NAM data. k-DPRA and KeratinoSensTM assays were used to predict LLNA effective concentration values (EC3) via the method of Natsch & Gerberick (2022). The assay results, in silico models, and available human and animal data were also leveraged into an integrated approach to predict sensitizer status for each chemical based on weight of evidence. PCSGs were derived by adjusting the predicted EC3 values to occupationally-relevant surface concentrations for chemicals predicted to be sensitizers. PCSGs can be compared to measured surface concentrations of potential sensitizers to better understand the risk of Airmen developing ACD from occupational exposures.

 

Fourth Presentation: Round Table Discussion

Presenters: Argel Islas-Robles, John Yin, Andrew Keebaugh

Attendees will have the opportunity to interact and discuss the presented topics with the presenters, including:

  • how the information from the NAMs was used in each training example;

  • use and value of pEC3 to generate decisions by each presenter's organization;

  • and lessons learned from these applications, and how can these lessons best be applied in the development, evaluation and use of NAMs.

Additionally, test cases with a focus on special situations will be shared in order to promote the discussion of pEC3 generation and use in Risk Assessment.

 

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