Estimation of reliability of predictions and model applicability domain evaluation in the analysis of acute toxicity (LD₅₀)

Abstract

This study presents a new type of acute toxicity (LD ₅₀) prediction that enables automated assessment of the reliability of predictions (which is synonymous with the assessment of the Model Applicability Domain as defined by the Organization for Economic Cooperation and Development). Analysis involved nearly 75,000 compounds from six animal systems (acute rat toxicity after oral and intraperitoneal administration; acute mouse toxicity after oral, intraperitoneal, intravenous, and subcutaneous administration). Fragmental Partial Least Squares (PLS) with 100 bootstraps yielded baseline predictions that were automatically corrected for non-linear effects in local chemical spaces–a combination called Global, Adjusted Locally According to Similarity (GALAS) modelling methodology. Each prediction obtained in this manner is provided with a reliability index value that depends on both compound's similarity to the training set (that accounts for similar trends in LD ₅₀ variations within multiple bootstraps) and consistency of experimental results with regard to the baseline model in the local chemical environment. The actual performance of the Reliability Index (RI) was proven by its good (and uniform) correlations with Root Mean Square Error (RMSE) in all validation sets, thus providing quantitative assessment of the Model Applicability Domain. The obtained models can be used for compound screening in the early stages of drug development and prioritization for experimental in vitro testing or later in vivo animal acute toxicity studies.

Keywords:

• QSAR
• acute toxicity
• rodent toxicity
• LD ₅₀
• model applicability domain
• reliability index

Acknowledgements

The team of authors is particularly thankful to Todd M. Martin, Alexander Tropsha and their colleagues for kindly providing the complete dataset, utilized in their recent study of rat acute toxicity by oral exposure 29.

Notes

Note

The Registry of Toxic Effects of Chemical Substances, RTECS®, is a compendium of toxicological data that was built and maintained by the National Institute of Occupational Safety and Health (NIOSH) from 1971 through January 2001. Symyx now produces the RTECS files using existing data selection criteria and rules established by NIOSH. The RTECS file is distributed quarterly to licensees under the terms of the License and Distribution Agreement entered into on October 29, 2001 between Symyx Technologies, Inc. and the United States Public Health Service within the Department of Health and Human Services.