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An in silico workflow for assessing the sensitisation potential of extractables and leachables

Chilton ML; Patel M; Oliveira A;

As part of a wider toxicological risk assessment to ensure patient safety, extractables and leachables (E&Ls) which are observed above the relevant qualification threshold need to be assessed for their sensitisation potential. This study sought to investigate whether in silico toxicity models could be used to predict the sensitisation hazard and potency potential of E&Ls. An extensive dataset of relevant chemicals was collated by combining and standardising two lists of E&Ls previously published by ELSIE and the PQRI, resulting in a dataset of 790 unique materials. Sensitisation data was then located where possible, resulting in 290 chemicals being associated with dermal sensitisation hazard information, 106 chemicals with dermal sensitisation potency information, and 47 chemicals with respiratory sensitisation information. Existing expert knowledge, in the form of structural alerts within Derek Nexus, was able to accurately predict both the dermal and respiratory sensitisation potential of the E&Ls. 75 different statistical models were also built, using several algorithms and descriptors, and trained on the available dermal sensitisation data. A number of these models proved able to accurately predict the sensitisation potential of the E&Ls, which were found to occupy the same chemical space as the training sets. Finally, hybrid approaches combining expert knowledge and statistical models were investigated, including a tiered system where the skin sensitisation alerts in Derek Nexus provided a hazard prediction, followed by a potency prediction resulting from an alert-based k-nearest neighbours model. The inclusion of the Dermal Sensitisation Thresholds as default, worst-case scenario predictions in cases where similar chemicals were lacking ensured that a prediction was provided for every chemical. It is hoped that this novel workflow, which combines expert knowledge, a statistical model and existing toxicity thresholds, will aid toxicologists when assessing the sensitisation potential of E&Ls administered by any route of administration.