RespiraTox – Development of a QSAR model to predict human respiratory irritants

• Published in: Regulatory toxicology and pharmacology 2022-02, Vol.128, p.105089-105089, Article 105089
• Main Authors: Wehr, Matthias M., Sarang, Satinder S., Rooseboom, Martijn, Boogaard, Peter J., Karwath, Andreas, Escher, Sylvia E.
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Animal Testing Alternatives - methods; Human respiratory irritation; In silico; Irritants - chemistry; Machine Learning; QSAR; Quantitative Structure-Activity Relationship; Read-across; Respiratory System - drug effects; Risk Assessment; Web application
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2021.105089

Respiratory irritation is an important human health endpoint in chemical risk assessment. There are two established modes of action of respiratory irritation, 1) sensory irritation mediated by the interaction with sensory neurons, potentially stimulating trigeminal nerve, and 2) direct tissue irritation. The aim of our research was to, develop a QSAR method to predict human respiratory irritants, and to potentially reduce the reliance on animal testing for the identification of respiratory irritants. Compounds are classified as irritating based on combined evidence from different types of toxicological data, including inhalation studies with acute and repeated exposure. The curated project database comprised 1997 organic substances, 1553 being classified as irritating and 444 as non-irritating. A comparison of machine learning approaches, including Logistic Regression (LR), Random Forests (RFs), and Gradient Boosted Decision Trees (GBTs), showed, the best classification was obtained by GBTs. The LR model resulted in an area under the curve (AUC) of 0.65, while the optimal performance for both RFs and GBTs gives an AUC of 0.71. In addition to the classification and the information on the applicability domain, the web-based tool provides a list of structurally similar analogues together with their experimental data to facilitate expert review for read-across purposes. •QSAR model development.•Highly curated in-vivo database.•Predict respiratory irritation.•Alternative method for hazard assessment.