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Roadmap Implementation: Acute Systemic Toxicity

Acute systemic toxicity tests are commonly used to evaluate the toxicity of chemicals, medical products, and other substances when ingested, inhaled, or absorbed through the skin.

The ICCVAM Acute Toxicity Workgroup (ATWG) coordinates implementation of the roadmap goals for acute systemic toxicity testing. The workgroup has members from eight ICCVAM agencies. NICEATM and the workgroup facilitate collaboration and engage with stakeholders to support development, acceptance, and utilization of new approach methodologies.

Definition of Testing Needs

The ATWG published a scoping document (Strickland et al. 2018) that identifies U.S. agency information requirements, needs, and decision contexts for acute systemic toxicity testing.

Identification of Available Alternative Tests and Computer Models

ICCVAM and NICEATM facilitate public-private partnerships to share data and information on the development and evaluation of alternative methods for acute systemic toxicity assessment. For example, EPA established a stakeholder group to discuss the development, evaluation, and implementation of alternatives for the “six-pack” of acute toxicity tests required for pesticide registration, including the three systemic toxicity tests. Activities within this group have informed EPA efforts toward adoption of alternative methods, such as guidance on waivers for dermal toxicity testing (described below).

NICEATM and ICCVAM partner with other organizations to hold workshops to discuss the state of the science for non-animal alternatives to current in vivo acute systemic toxicity tests and implementation progress. These include:

  • A 2015 workshop (summarized in Hamm et al. 2017) identified resources necessary to advance identification and implementation of alternative methods for acute systemic toxicity testing, including high-quality reference data, training on use and interpretation of computational approaches, and global harmonization of testing requirements.
  • A 2016 webinar series and workshop (summarized in Clippinger et al. 2018a) focused on alternatives for inhalation toxicity testing. The webinar series reviewed mechanisms of acute inhalation toxicity, regulatory needs for acute inhalation toxicity data, and available alternative approaches. The subsequent workshop identified activities needed to develop alternative testing strategies that will meet the information needs of regulatory agencies. Workgroups were established to coordinate these activities; some outcomes are described below under “Developing IATA and Defined Approaches."
  • A 2018 workshop (summarized in Kleinstreuer et al. 2018) presented the results of a global project (described below) to develop in silico models for acute oral systemic toxicity. Insights on the reproducibility of in vivo studies were also discussed.
Compilation of Reference Data

Development of new testing approaches requires high-quality data. One of the follow-up activities from the inhalation toxicity workshop was to gather acute inhalation toxicity data, and these efforts are underway. NICEATM and the EPA NCCT compiled acute oral LD50 data from multiple curated databases, and NICEATM has also compiled EPA data on pesticide formulations. These data sets are available through the NICEATM Integrated Chemical Environment (ICE).

Efforts are ongoing to establish public-private partnerships to share acute systemic toxicity data. Such partnerships could provide data for evaluating alternative methods for a broader range of substances than is available from the scientific literature.

Developing IATA and Defined Approaches

NICEATM and ICCVAM agencies are considering a number of different approaches to reduce animal use for required testing. These include using integrated approaches to testing and assessment (IATA) and defined approaches, which enable prediction of acute systemic toxicity through high-throughput screening assays and in silico models.

NICEATM continues to work with the ATWG to quantify and define the variability of in vivo endpoints from acute systemic toxicity bioassays, such as oral LD50 values. These analyses provide important insight into the reproducibility of the in vivo tests and add context for appropriately evaluating the performance of non-animal approaches that are under development.

  • Analyses of curated acute oral toxicity data are in progress; a manuscript will be submitted for publication in 2019.
  • Curation of acute inhalation toxicity data is ongoing, with a data release via ICE planned in 2019. This is a follow-up activity from the 2016 workshop described above.

One product from the 2016 inhalation toxicity workshop was a state-of-the-science manuscript (Clippinger et al. 2018b), which describes relevant adverse outcome pathways that could be used to guide development of non-animal testing strategies for inhalation toxicity. The paper also summarizes the toolbox of in vitro and in silico models that can be used to assess key events from inhalation exposure to toxic outcomes.

In November 2017, the ATWG initiated a global project to develop in silico models of acute oral systemic toxicity that predict five specific endpoints identified by ATWG members as being relevant to U.S. regulatory agencies. Predictive models were developed and evaluated in both a qualitative and quantitative manner, using a large body of rat oral acute toxicity data collected by NICEATM and NCCT. Models developed for the project that met criteria defined by the project organizing committee were used to generate consensus predictions for the acute oral toxicity endpoints of interest. Models were presented at an 2018 workshop (summarized in Kleinstreuer et al. 2018) and the consensus predictions generated for the project are available via the Open Structure-Activity/Property Relationship App (OPERA), a free and open-source QSAR tool. While the predictions will be made available via ICE and the EPA’s CompTox Dashboard, the consensus models will be made available and described in a manuscript expected to be submitted for publication in 2019.

Addressing Regulatory and Other Challenges

Other approaches being used by ICCVAM agencies to reduce animal use for required testing include non-testing approaches such as waivers. For example, the EPA Office of Pesticide Products issued guidance in 2016 for waiving the acute dermal toxicity test for pesticide formulations, based on a NICEATM analysis that indicated that oral acute toxicity tests were often more informative and sensitive.

A common theme that has emerged from past NICEATM workshops is the need for training opportunities to inform industry and regulatory staff about the use and interpretation of in vitro and in silico data and defined approaches. Thus, efforts to facilitate regulatory acceptance and use of defined approaches and other alternative methods will include the development of training materials and technical support to assist agencies in issuing guidance.