Citation:

Ponder, J., R. Rajagopal, M. Singal, N. Baker, S. Cochrane, G. Patlewicz, AND K. Sullivan. “In Litero” Screening: Retrospective Evaluation of Clinical Evidence to Establish a Reference List of Chemical Respiratory Sensitizers. Frontiers - Women in Regulatory Toxicology, N/A, N/A, December 01, 2021.

Impact/Purpose:

The goal of this product is to develop datasets and QSAR models to support hazard estimation. Prediction of key hazard endpoints is often necessary due to the sparsity of available experimental toxicity data.  Such models while less desirable than concrete measured values often provide the only quantitative or binary hazard metrics for the vast majority of chemicals in the environment.  As interest in large scale evaluation and prioritization of potential toxicants increases, the development of reliable models following QSAR best practices accepted in the community for hazard endpoints is necessary to provide defensible hazard estimations to support risk–based prioritization. This product provides regulatory scientists, students and researchers with the ability to effectively access and exploit the many in silico data streams to support different regulatory purposes and supports current Agency efforts to reduce mammal study requests by 30% by 2025, and completely eliminate all mammal study requests and funding by 2035.

Description:

Despite decades of investigation, test methods to identify chemical respiratory allergens remain an unmet regulatory need. A critical advantage to the development of human cell and tissue culture models for sensitization is the ability to improve the accuracy of translation of results to real-world scenarios. In order to support the evaluation of test methods in development, we sought to establish a reference set of low molecular weight respiratory sensitizers based on clinically verified case reports of occupational asthma. In this context, we have developed an “in litero” approach to identify cases of occupational exposures leading to respiratory sensitization in clinical literature. We utilized the EPA-developed Abstract Sifter literature review tool and standardized search terms to maximize the retrieval of publications relevant to chemical respiratory allergy in humans for a list of low-molecular-weight chemicals suspected of inducing respiratory sensitization. The literature for these candidate chemicals was further queried and sifted to identify relevant case reports and studies, and then evaluated to apply selection criteria. Stringent clinical diagnostic criteria were defined around exposure history, respiratory effects, and specific immune response to conclusively demonstrate occupational asthma as a result of sensitization, rather than irritation. These defined criteria were applied systematically to answer the central query: has this chemical been shown to cause respiratory sensitization in clinical literature? Further annotation was included to identify frequency of reports.  This approach successfully identified 28 compounds that can be considered as likely respiratory sensitizers and used to evaluate the relevance of in vitro methods to identify respiratory sensitizers. Another 155 chemicals were found to have evidence suggestive of respiratory sensitization, which was sometimes not well-distinguished from respiratory irritation or sensitization arising from confounding exposures. Further, these results have immediate implications for the development and refinement of in silico predictive tools to distinguish between skin and respiratory sensitizers. A comparison of the protein binding mechanisms of our identified “in litero” respiratory sensitizers shows that acylation is a prevalent protein binding mechanism, in contrast to Michael addition and Schiff base formation common to skin sensitizers. Overall, this approach provides an exemplary method to evaluate and apply human clinical data as part of the weight-of-evidence towards establishing reference chemical lists. This abstract does not necessarily reflect U.S. EPA policy.

Record Details: