Abstract
SummaryThe public data on skin sensitization from REACH registrations already included 19,111 studies on skin sensitization in December 2014, making it the largest repository of such data so far (1,470 substances with mouse LLNA, 2,787 with GPMT, 762 with both in vivo and in vitro and 139 with only in vitro data). 21% were classified as sensitizers. The extracted skin sensitization data was analyzed to identify relationships in skin sensitization guidelines, visualize structural relationships of sensitizers, and build models to predict sensitization.A chemical with molecular weight > 500 Da is generally considered non-sensitizing owing to low bioavailability, but 49 sensitizing chemicals with a molecular weight > 500 Da were found.A chemical similarity map was produced using PubChem’s 2D Tanimoto similarity metric and Gephi force layout visualization. Nine clusters of chemicals were identified by Blondel’s module recognition algorithm revealing wide module-dependent variation.Approximately 31% of mapped chemicals are Michael’s acceptors but alone this does not imply skin sensitization. A simple sensitization model using molecular weight and five ToxTree structural alerts showed a balanced accuracy of 65.8% (specificity 80.4%, sensitivity 51.4%), demonstrating that structural alerts have information value.A simple variant of k-nearest neighbors outperformed the ToxTree approach even at 75% similarity threshold (82% balanced accuracy at 0.95 threshold). At higher thresholds, the balanced accuracy increased. Lower similarity thresholds decrease sensitivity faster than specificity.This analysis scopes the landscape of chemical skin sensitization, demonstrating the value of large public datasets for health hazard prediction.
Highlights
While computational toxicology has recently seen the collection of several large-scale datasets (e.g., US EPA’s ToxCast, the Tox21 alliance of US agencies), the data collected by REACH (Regulation (EC) 1907/2006), owing to its legislative nature as a central repository for testing data, is the largest collection of toxicology data today relating to in vitro and in vivo studies
3.1 Sensitization data exists in greater abundance in the REACH dataset than in other existing datasets REACH requires assessment of skin sensitization potential for all registered substances (REACH Annex VII, REACH Annex VIII)
Even in case of data-waiving for skin sensitization, which REACH allows under certain circumstances, substance dossiers collect many studies related to sensitization
Summary
While computational toxicology has recently seen the collection of several large-scale datasets (e.g., US EPA’s ToxCast, the Tox alliance of US agencies), the data collected by REACH (Regulation (EC) 1907/2006), owing to its legislative nature as a central repository for testing data, is the largest collection of toxicology data today relating to in vitro and in vivo studies. We seek to demonstrate the extent and diversity of the public REACH dataset – a dataset that far surpasses most existing datasets used for computational toxicology – and show, as a case study, how an open-access REACH program would allow profound change in the analysis of skin sensitization by chemical substances. Using REACH data, we were able to find in vivo skin sensitization data for thousands of chemicals.
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