A scheme to evaluate structural alerts to predict toxicity – Assessing confidence by characterising uncertainties

Highlights

• Structural alerts are useful tools for predictive toxicology.

• 12 criteria to evaluate structural alerts have been identified.

• A strategy to determine confidence of structural alerts is presented.

• Different use cases require different characteristics of structural alerts.

• A Scheme to Evaluate Structural Alerts to Predict Toxicity – Assessing Confidence By Characterising Uncertainties.

Abstract

Structure-activity relationships (SARs) in toxicology have enabled the formation of structural rules which, when coded as structural alerts, are essential tools in in silico toxicology. Whilst other in silico methods have approaches for their evaluation, there is no formal process to assess the confidence that may be associated with a structural alert. This investigation proposes twelve criteria to assess the uncertainty associated with structural alerts, allowing for an assessment of confidence. The criteria are based around the stated purpose, description of the chemistry, toxicology and mechanism, performance and coverage, as well as corroborating and supporting evidence of the alert. Alerts can be given a confidence assessment and score, enabling the identification of areas where more information may be beneficial. The scheme to evaluate structural alerts was placed in the context of various use cases for industrial and regulatory applications. The analysis of alerts, and consideration of the evaluation scheme, identifies the different characteristics an alert may have, such as being highly specific or generic. These characteristics may determine when an alert can be used for specific uses such as identification of analogues for read-across or hazard identification.