Journal
ENVIRONMENTAL HEALTH PERSPECTIVES
Volume 129, Issue 4, Pages -Publisher
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/EHP8495
Keywords
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Funding
- NIEHS, NIH
- NCATS, NIH
- Integrated Laboratory Systems under NIEHS contract [HHSN273201500010C]
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The international collaboration in developing in silico models for predicting acute oral toxicity, resulting in the CATMoS, has demonstrated high performance in terms of accuracy and robustness. This modeling suite is being evaluated by regulatory agencies as a potential replacement for in vivo rat acute oral toxicity studies.
BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to he 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. In silica models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (live) categories, very toxic chemicals [LD50 (LD50 <= 50 mg/kg)], and nontoxic chemicals (LD50 > 2,000 mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: 'the resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new: and untested chemicals to be made.
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