Abstract
The Cocultured Activation Test (COCAT) consists of cocultured HaCaT (human keratinocyte cell line) and THP-1 cells (surrogate of antigen presenting cells). Individually, these cell lines are used to address key event 2 and 3 of the skin sensitization Adverse Outcome Pathway (AOP). Their exposure in coculture was found to have the potential to increase their response to sensitizing chemicals, enable the detection of pro-haptens and support the identification of skin sensitization potency. The present study was undertaken to assess the predictive capacity of COCAT to both skin sensitization hazard and potency and to assess the intra-laboratory reproducibility of COCAT based on the blind testing of chemicals. Results showed a reproducibility between runs of 80 % for 15 coded chemicals. 100% sensitivity (9/9), 75 % specificity (3/4) and 92.3 % accuracy (12/13) was found for skin sensitization hazard prediction, while the tests of two chemicals were inconclusive. Including additional chemicals tested during the optimization phase in addition to the blind tested chemicals, the skin sensitization UN GHS sub-categories were correctly predicted for 85.7 % (12/14) Sub-category 1A chemicals, 83.3 % (10/12) Sub-category 1B chemicals and 92.3 % (12/13) 'No Category' chemicals, resulting in an overall accuracy of 87.4 % (34/39). The present study shows the COCAT to be a promising method for the identification of skin sensitization hazard and potency sub-categorization according to the UN GHS classification.
Highlights
Skin sensitization induced by chemicals represents an important endpoint for consumer and occupational safety assessment
The predictive capacity of the Cocultured Activation Test (COCAT) in the blind study was assessed by comparing the in vitro predictions with Local Lymph Node Assay (LLNA) and human reference results, from which identical skin sensitization potential/hazard was concluded for the 15 tested chemicals
Using this cut-off to distinguish skin sensitizers with UN GHS sub-category 1A from 1B allowed to correctly predict 12 of 13 skin sensitizers of sub-category 1A and 11 of 13 skin sensitizers of sub-category 1B, representing a total of 23 of 26 correctly predicted sub-category 1A or 1B sensitizers (85.5%)
Summary
Skin sensitization induced by chemicals represents an important endpoint for consumer and occupational safety assessment. For regulatory purposes, it can be characterized by hazard categorization according to, e.g., the UN GHS classification scheme (UN, 2017) and/or by quantitative risk assessment, for which a deeper understanding of the potency of the sensitizer is needed (as, e.g., for cosmetic ingredients). A number of OECD Test Guidelines (TG) have been adopted that address the three major key events of the adverse outcome pathway (AOP) leading to skin sensitization. These are i) the covalent binding of electrophilic substances to nucleophilic centers in skin proteins as the molecular initiating event or first key event (OECD, 2019), ALTEX 36(4), 2019
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