STopTox: An in Silico Alternative to Animal Testing for Acute Systemic and Topical Toxicity

BACKGROUND: Modern chemical toxicology is facing a growing need to Reduce, Refine, and Replace animal tests (Russell 1959) for hazard identification. The most common type of animal assays for acute toxicity assessment of chemicals used as pesticides, pharmaceuticals, or in cosmetic products is known as a "6-pack" battery of tests, including three topical (skin sensitization, skin irritation and corrosion, and eye irritation and corrosion) and three systemic (acute oral toxicity, acute inhalation toxicity, and acute dermal toxicity) end points. METHODS: We compiled, curated, and integrated, to the best of our knowledge, the largest publicly available data sets and developed an ensemble of quantitative structure-activity relationship (QSAR) models for all six end points. All models were validated according to the Organisation for Economic Co-operation and Development (OECD) QSAR principles, using data on compounds not included in the training sets. RESULTS: In addition to high internal accuracy assessed by cross-validation, all models demonstrated an external correct classification rate ranging from 70% to 77%. We established a publicly accessible Systemic and Topical chemical Toxicity (STopTox) web portal (https://stoptox.mml.unc.edu/) integrating all developed models for 6-pack assays. CONCLUSIONS: We developed STopTox, a comprehensive collection of computational models that can be used as an alternative to in vivo 6-pack tests for predicting the toxicity hazard of small organic molecules. Models were established following the best practices for the development and validation of QSAR models. Scientists and regulators can use the STopTox portal to identify putative toxicants or nontoxicants in chemical libraries of interest. https://doi.org/10.1289/EHP9341

STopTox: An In-Silico Alternative to Animal Testing for Acute Systemic and TOPical TOXicity

Since 2009, animal testing for cosmetic products has been prohibited in Europe, and in 2016, US EPA announced their intent to modernize the so-called "6-pack" of acute toxicity tests (acute oral toxicity, acute dermal toxicity, acute inhalation toxicity, skin irritation and corrosion, eye irritation and corrosion, and skin sensitization) and expand acceptance of alternative methods to reduce animal testing of pesticides. We have compiled, curated, and integrated the largest publicly available dataset and developed an ensemble of QSAR models for all six endpoints. All models were validated according to the OECD QSAR principles and tested using newly identified data on compounds not included in the training sets. We have established a publicly accessible Systemic and Topical chemical Toxicity (STopTox) web portal (https://stoptox.mml.unc.edu/) integrating all developed models for “6-pack” assays. This portal can be used by scientists and regulators to identify putative toxicants or non-toxicants in chemical libraries of interest.</p