Examining animal testing for risk assessment: A WC-12 workshop report.

In toxicology and regulatory testing, the use of animal methods has been both a cornerstone and a subject of intense debate. To continue this discourse a panel and audience representing scientists from various sectors and countries convened at a workshop held during the 12th World Congress on Alternatives and Animal Use in the Life Sciences (WC-12). The ensuing discussion focused on the scientific and ethical considerations surrounding the necessity and responsibility of defending the creation of new animal data in regulatory testing.

Evaluating H295R steroidogenesis assay data for robust interpretation.

The in vitro H295R steroidogenesis assay (OECD TG 456) is used to determine a chemical's potential to interfere with steroid hormone synthesis/metabolism. As positive outcomes in this assay can trigger significant higher tiered testing, we compiled a stakeholder database of reference and test item H295R data to characterize assay outcomes. Information concerning whether a Level 5 reproductive toxicity study was triggered due to a positive outcome in the H295R assay was also included.

Weight of evidence for cross-species conservation of androgen receptor-based biological activity.

The U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP) is tasked with assessing chemicals for their potential to perturb endocrine pathways, including those controlled by androgen receptor (AR).

Principles and Procedures for Assessment of Acute Toxicity Incorporating Methods.

Acute models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing how to perform and document an analysis. To address this issue, a framework for an acute toxicity hazard assessment is proposed.

Data curation to support toxicity assessments using the Integrated Chemical Environment.

Humans are exposed to large numbers of chemicals during their daily activities. To assess and understand potential health impacts of chemical exposure, investigators and regulators need access to reliable toxicity data. In particular, reliable toxicity data for a wide range of chemistries are needed to support development of new approach methodologies (NAMs) such as computational models, which offer increased throughput relative to traditional approaches and reduce or replace animal use.

A geospatial modeling approach to quantifying the risk of exposure to environmental chemical mixtures via a common molecular target.

In the real world, individuals are exposed to chemicals from sources that vary over space and time. However, traditional risk assessments based on in vivo animal studies typically use a chemical-by-chemical approach and apical disease endpoints. New approach methodologies (NAMs) in toxicology, such as in vitro high-throughput (HTS) assays generated in Tox21 and ToxCast, can more readily provide mechanistic chemical hazard information for chemicals with no existing data than in vivo methods.

Evaluation of Variability Across Rat Acute Oral Systemic Toxicity Studies.

Regulatory agencies rely upon rodent in vivo acute oral toxicity data to determine hazard categorization, require appropriate precautionary labeling, and perform quantitative risk assessments. As the field of toxicology moves toward animal-free new approach methodologies (NAMs), there is a pressing need to develop a reliable, robust reference data set to characterize the reproducibility and inherent variability in the in vivo acute oral toxicity test method, which would serve to contextualize results and set expectations regarding NAM performance. Such a data set is also needed for training and evaluating computational models.

Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using to Extrapolation.

methods offer opportunities to provide mechanistic insight into bioactivity as well as human-relevant toxicological assessments compared to animal testing. One of the challenges for this task is putting bioactivity data in an exposure context, for which to extrapolation (IVIVE) translates bioactivity to clinically relevant exposure metrics using reverse dosimetry. This study applies an IVIVE approach to the toxicity assessment of ingredients and their mixtures in e-cigarette (EC) aerosols as a case study.

CATMoS: Collaborative Acute Toxicity Modeling Suite.

Background: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests.

An evaluation of the performance of selected (Q)SARs/expert systems for predicting acute oral toxicity.

Multiple US agencies use acute oral toxicity data in a variety of regulatory contexts. One of the ad-hoc groups that the US Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) established to implement the ICCVAM Strategic Roadmap was the Acute Toxicity Workgroup (ATWG) to support the development, acceptance, and actualisation of new approach methodologies (NAMs). One of the ATWG charges was to evaluate and methods for predicting rat acute systemic toxicity.

An integrated chemical environment with tools for chemical safety testing.

Moving toward species-relevant chemical safety assessments and away from animal testing requires access to reliable data to develop and build confidence in new approaches. The Integrated Chemical Environment (ICE) provides tools and curated data centered around chemical safety assessment. This article describes updates to ICE, including improved accessibility and interpretability of in vitro data via mechanistic target mapping and enhanced interactive tools for in vitro to in vivo extrapolation (IVIVE).

State of the science on alternatives to animal testing and integration of testing strategies for food safety assessments: Workshop proceedings.

Rapidly evolving technological methods and mechanistic toxicological understanding have paved the way for new science-based approaches for the determination of chemical safety in support of advancing public health. Approaches including read-across, high-throughput screening, in silico models, and organ-on-a-chip technologies were addressed in a 2017 workshop focusing on how scientists can move effectively toward a vision for 21st century food safety assessments. The application of these alternative methods, the need for further development of standardized practices, and the interpretation and communication of results were addressed.

Incorporating new approach methodologies in toxicity testing and exposure assessment for tiered risk assessment using the RISK21 approach: Case studies on food contact chemicals.

Programs including the ToxCast project have generated large amounts of in vitro high‒throughput screening (HTS) data, and best approaches for the interpretation and use of HTS data, including for chemical safety assessment, remain to be evaluated. To fill this gap, we conducted case studies of two indirect food additive chemicals where ToxCast data were compared with in vivo toxicity data using the RISK21 approach. Two food contact substances, sodium (2-pyridylthio)-N-oxide and dibutyltin dichloride, were selected, and available exposure data, toxicity data, and model predictions were compiled and assessed.

SAR and QSAR modeling of a large collection of LD rat acute oral toxicity data.

The median lethal dose for rodent oral acute toxicity (LD50) is a standard piece of information required to categorize chemicals in terms of the potential hazard posed to human health after acute exposure. The exclusive use of in vivo testing is limited by the time and costs required for performing experiments and by the need to sacrifice a number of animals. (Quantitative) structure-activity relationships [(Q)SAR] proved a valid alternative to reduce and assist in vivo assays for assessing acute toxicological hazard.

Exploring current read-across applications and needs among selected U.S. Federal Agencies.

Read-across is a well-established data gap-filling technique applied for regulatory purposes. In US Environmental Protection Agency's New Chemicals Program under TSCA, read-across has been used extensively for decades, however the extent of application and acceptance of read-across among U.S.

Nonanimal Models for Acute Toxicity Evaluations: Applying Data-Driven Profiling and Read-Across.

Background: Low-cost, high-throughput in vitro bioassays have potential as alternatives to animal models for toxicity testing. However, incorporating in vitro bioassays into chemical toxicity evaluations such as read-across requires significant data curation and analysis based on knowledge of relevant toxicity mechanisms, lowering the enthusiasm of using the massive amount of unstructured public data.

Objective: We aimed to develop a computational method to automatically extract useful bioassay data from a public repository (i.

Predictive Models for Acute Oral Systemic Toxicity: A Workshop to Bridge the Gap from Research to Regulation.

In early 2018, the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) published the "Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States" (ICCVAM 2018). Cross-agency federal workgroups have been established to implement this roadmap for various toxicological testing endpoints, with an initial focus on acute toxicity testing. The ICCVAM acute toxicity workgroup (ATWG) helped organize a global collaboration to build predictive in silico models for acute oral systemic toxicity, based on a large dataset of rodent studies and targeted towards regulatory needs identified across federal agencies.

Scientific advances and challenges in safety evaluation of food packaging materials: Workshop proceedings.

Packaging is an indispensable component of the food manufacturing and food supply process. This scientific workshop was convened to bring together scientists from government, academia, and industry to discuss the state of the science regarding the safety of food packaging, prompted by rapidly advancing research to improve food packaging that continues to impact packaging technology, toxicology, exposure, risk assessment, and sustainability. The opening session focused on scientific challenges in the safety assessment of food packaging materials.

Challenges for Integrating Immunotoxicology into the Twenty-First-Century Toxicology Testing Paradigm.

An emerging emphasis on mechanism-focused and human-relevant alternatives to animal use in toxicology underlies the toxicology testing in the twenty-first-century initiative. Herein we describe in vitro high-throughput screening programs seeking to address this goal, as well as strategies established to integrate assay results to build weight of evidence in support of hazard assessment. Furthermore, we discuss unique challenges facing the application of such alternatives for assessing immunotoxicity given the complexity of immune responses.

A hybrid gene selection approach to create the S1500+ targeted gene sets for use in high-throughput transcriptomics.

Changes in gene expression can help reveal the mechanisms of disease processes and the mode of action for toxicities and adverse effects on cellular responses induced by exposures to chemicals, drugs and environment agents. The U.S.

High-Throughput H295R Steroidogenesis Assay: Utility as an Alternative and a Statistical Approach to Characterize Effects on Steroidogenesis.

The U.S. Environmental Protection Agency Endocrine Disruptor Screening Program and the Organization for Economic Co-operation and Development (OECD) have used the human adrenocarcinoma (H295R) cell-based assay to predict chemical perturbation of androgen and estrogen production.

Curation of food-relevant chemicals in ToxCast.

High-throughput in vitro assays and exposure prediction efforts are paving the way for modeling chemical risk; however, the utility of such extensive datasets can be limited or misleading when annotation fails to capture current chemical usage. To address this data gap and provide context for food-use in the United States (US), manual curation of food-relevant chemicals in ToxCast was conducted. Chemicals were categorized into three food-use categories: (1) direct food additives, (2) indirect food additives, or (3) pesticide residues.