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Towards an IATA for Chemical Respiratory Sensitization: Establishment of Reference Chemicals to Evaluate In Vitro and In Silico Approaches
Sullivan, K., N. Baker, S. Cochrane, S. Enoch, J. Ezendam, G. Patlewicz, E. Roggen, R. Settivari, AND K. Sewald. Towards an IATA for Chemical Respiratory Sensitization: Establishment of Reference Chemicals to Evaluate In Vitro and In Silico Approaches. Presented at 2018 SOT National Meeting, San Antonio, TX, March 11 - 15, 2018. https://doi.org/10.23645/epacomptox.6987158
Motivation and methods for finding reference chemicals for respiratory sensitization.
Public health and regulatory needs require an approach to detect respiratory sensitizers and discriminate them from dermal sensitizers; however no single method or strategy is generally accepted. An Adverse Outcome Pathway (AOP) for sensitization of the respiratory tract by low molecular weight organic chemicals has been published and identifies several promising in vitro methods. Most of these have only been assessed with a few commonly-referenced respiratory sensitizers such as toluene diisocyanate and trimellitic anhydride. In order to evaluate the utility of these methods, we have set out to build a more comprehensive list of reference chemicals, including known respiratory irritants, non-sensitizers, and dermal sensitizers. The ideal list of respiratory sensitizers will cover a range of chemical classes, include soft and hard electrophiles, those with an ability to cross-link proteins, volatile chemicals, and some representing known challenges in the field, such as respiratory sensitizers thought to elicit effects through dermal exposure and those for which specific-IgE has not been detected in humans. To build the list, we are conducting a review of established structure-based profilers, recent literature, and human clinical reports, with a focus on findings verified in humans to maximize translatability to human health outcomes. We are also making use of the Abstract Sifter literature review tool to identify additional potential respiratory sensitizers. Briefly, a list of 92 chemicals thought to be respiratory sensitizers was used to query the EPA’s LitDB database of MeSH terms from PubMed to extract all the adverse effects (AEs) associated with the chemicals. The set of AEs that occurred in over 15 of the chemicals was used to query the entire database of MeSH AEs for all chemicals. Any chemical with at least one of the annotated AEs was selected. The resulting list of over 7,000 chemicals was weighted by AE and article count. The top 500 chemicals were selected for manual review. This list is an important step towards a robust assessment of potential test methods and the creation of internationally-harmonized integrated approaches for the detection of chemical respiratory sensitizers. This abstract does not necessarily represent U.S. EPA policy.
RS REF CHEMS POSTER 2018_GP.PDF (PDF,NA pp, 242.736 KB, about PDF)
Record Details:Record Type: DOCUMENT (PRESENTATION/POSTER)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY