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Predictive Models for Acute Oral Systemic Toxicity

Collaborative Acute Toxicity Modeling Suite (CATMoS)

  • Project participants and others interested in the Predictive Models for Acute Oral Systemic Toxicity project attended a workshop of the same name at the National Institutes of Health in Bethesda, Maryland, on April 11-12, 2018. Read the workshop report (Kleinstreuer et al. 2018) in Computational Toxicology.
  • A video recording and slides are available from a January 2020 webinar titled “CATMoS: Development and Use of the Collaborative Acute Toxicity Modeling Suite,” presented by the PETA International Science Consortium (PETA-ISC). In this webinar, NICEATM Acting Director Nicole Kleinstreuer and Kamel Mansouri, ILS (contractor supporting NICEATM), discussed development of CATMoS and demonstrated how to use the modeling suite to generate acute oral toxicity predictions. Links to recordings of all webinars in the PETA-ISC series on “Use of New Approach Methodologies in Risk Assessment” are available on the PETA-ISC website

The ICCVAM Acute Toxicity Workgroup organized a global project to develop in silico models of acute oral systemic toxicity that predict five specific endpoints needed by regulatory agencies (described below under “Objectives”). NICEATM invited scientists to develop in silico models that predict any or all of these endpoints.

NICEATM and the EPA National Center for Computational Toxicology (NCCT; now part of the EPA Center for Computational Toxicology & Exposure) collected a large body of rat oral acute toxicity data. Subsets of these data were used by project participants to build and test their models, and by NICEATM and the project organizing committee to evaluate the models.

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 to regulatory agencies. Details of how the consensus predictions were generated will be described in a journal article expected to be published in 2021 (Mansouri et al., submitted).

The consensus models are available in the Collaborative Acute Toxicity Modeling Suite (CATMoS), a free resource for screening organic chemicals for acute oral toxicity. CATMoS is implemented in v2.0 of the Open Structure-Activity/Property Relationship App (OPERA), a free and open-source QSAR tool (Mansouri et al. 2018). OPERA v2.0 can be downloaded from the NIEHS Github repository. The consensus predictions are also available via NICEATM's Integrated Chemical Environment and will be available via EPA's CompTox Dashboard.

Project participants publishing descriptions of their models should cite, as appropriate:

  • This webpage
  • The report from the April 2018 workshop (Kleinstreuer et al. 2018)
  • The forthcoming journal article describing generation of the consensus predictions (Mansouri et al., submitted)
Background and Scope

One of ICCVAM’s high priority efforts is to develop alternative test methods for the EPA “six-pack” tests: acute oral, dermal, and inhalation systemic toxicity tests and tests to determine eye and skin irritation and skin sensitization. These tests are required by regulatory agencies worldwide and represent the highest cumulative animal use across chemical sectors.

As part of the effort to develop alternative methods for predicting acute oral systemic toxicity, NICEATM and NCCT have collected a large body of rat acute oral lethality data that can be used to develop predictive in silico models. Recognizing that no single modeling approach is likely to address all regulatory endpoints nor predict toxicity of all classes of chemicals, the ICCVAM Acute Toxicity Workgroup organized an international modeling project to predict acute oral toxicity endpoints using these data. This project is a collaborative effort between member-teams of the consortium to combine efforts and leverage each model’s strengths while overcoming the limitations of any individual approach.


The objective of this project was to leverage the combined expertise of the international modeling community to develop predictive models for acute oral toxicity. Based on the range of regulatory criteria and decision contexts used by ICCVAM agencies, a total of five different modeling endpoints were identified for project models. Participants built models to predict one or more of the following endpoints:

  • Very toxic (<50 mg/kg vs. all others)
  • Nontoxic (>2000 mg/kg vs. all others)
  • LD50 point estimates
  • Hazard categories under the EPA classification system (n=4) 
  • Hazard categories under the GHS classification system (n=5; Category 5 and Not Classified combined into a single category)
Timeline and Resources

Detailed project information (updated November 20, 2017)

Questions and answers for participants (December 2017)

November 17, 2017: Release of training data set

December 15, 2017: Release of prediction data set

February 16, 2018Deadline (updated) for participants to submit model results on training and prediction sets, model documentation, and workshop abstract.

March 9, 2018: Project organizing committee notifies participants selected for platform presentations at the April workshop

March 27, 2018: Release of evaluation data set

April 11-12, 2018: Predictive Models for Acute Oral Systemic Toxicity Workshop, Natcher Conference Center, National Institutes of Health, Bethesda, Maryland