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Weight-of-Evidence Analysis for the Development of a Reference List of Chemical Respiratory Sensitizers
Citation:
Ponder, J., R. Rajagopal, S. Cochrane, M. Singal, N. Baker, G. Patlewicz, E. Roggen, AND K. Sullivan. Weight-of-Evidence Analysis for the Development of a Reference List of Chemical Respiratory Sensitizers. SOT, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.22630639
Impact/Purpose:
There remains a lack of internationally harmonized approaches to identify chemical respiratory allergens. Approaches are needed for determining the potential of a low molecular weight (LMW) compound to sensitize the respiratory tract and hence the need for hazard labelling, potency assessment, and the definition of thresholds for reactivity as well as distinguishing respiratory from dermal sensitizers. A limiting factor for the development of test methods for chemical respiratory sensitization is the scarcity of well-studied chemicals to use in a defined reference set of known sensitizers and non-sensitizers. To address this limitation, we have recently made significant progress in synthesizing clinical literature to expand the list of human respiratory sensitizers, finding 28 unique clinical respiratory sensitizers using an ”in litero” screening approach with defined clinical diagnostic criteria. This reference list will be vital to the evaluation NAMs to identify respiratory sensitizers in a regulatory context. This will work will directly impact EPA’s program office partners by integrating and delivering NAM based approaches (i.e., conceptual scientific workflows) in areas of regulatory jurisdiction that have large data gaps (i.e., alternative assessments in OCSPP, OPPT, OLEM, OW, etc).
Description:
Despite high regulatory need, there remains a lack of internationally harmonized approaches to identify chemical respiratory allergens. Depending on the regulatory context, approaches are needed for determining the potential of a low molecular weight (LMW) compound to sensitize the respiratory tract and hence the need for hazard labelling, potency assessment, and the definition of thresholds for reactivity as well as distinguishing respiratory from dermal sensitizers, in particular forLMW chemicals. This unmet need presents a unique opportunity to apply New Approach Methodologies (NAMs) and human biological understanding ab initio to the development of regulatory guidelines and approaches needed to protect consumer and worker health. An Adverse Outcome Pathway has been outlined to identify hazard identification approaches to assess chemicals for this endpoint. Briefly, the AOP for respiratory sensitization follows a similar path to dermal sensitization, from protein binding to immune activation, instead resulting in IgE mediated bronchial hypersensitivity rather than T-cell mediated contact dermatitis. However, evidence suggests that skin and respiratory sensitization pathways may diverge at early key events, and recent efforts have sought to characterize the specifics regarding protein identity and chemical reactivity mechanisms that may be informative for distinguishing skin and respiratory sensitizers. A major limiting factor for the development of test methods for chemical respiratory sensitization is the scarcity of well-studied chemicals to use in a defined reference set of known sensitizers and non-sensitizers. To address this limitation, we have recently made significant progress in synthesizing clinical literature to expand the list of human respiratory sensitizers, finding 28 unique clinical respiratory sensitizers using an ”in litero” screening approach with defined clinical diagnostic criteria. A highly significant (p < 0.001) enrichment for acylation over other covalent binding mechanisms was observed in the identified clinical respiratory sensitizers. This approach also identified 153 chemicals with clinical evidence that was suggestive, but not conclusive, of respiratory sensitization. Using the QSAR Toolbox to compare the reactivity mechanisms of these chemicals identified 21 additional chemicals with suggestive clinical evidence that share this covalent binding mechanism. Herein we present additional positive chemicals identified from a weight-of-evidence analysis of in silico, in vitro, and in vivo studies, and a systematic method to establish a list of non-sensitizers for test method evaluation. This reference list will be vital to the evaluation NAMs to identify respiratory sensitizers. This abstract does not reflect EPA policy.
URLs/Downloads:
DOI: Weight-of-Evidence Analysis for the Development of a Reference List of Chemical Respiratory Sensitizers
PONDER_SOT2023 D04.PDF (PDF, NA pp, 1108.154 KB, about PDF)