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In silico prediction of DILI: extraction of histopathology data from preclinical toxicity studies of the eTOX database for new in silico models of hepatotoxicity

: Sullivan, K.; Baker, N.; Cochrane, S.; Enoch, Steven J.; Ezendam, Janine; Patlewicz, G.; Roggen, Erwin L.; Settivari, R.; Sewald, Katherina

The Toxicologist 162 (2018), No.1, Late-Breaking Supplement, pp.14-15, Abstract 3340
ISSN: 0731-9193
Society of Toxicology (Annual Meeting) <57, 2018, San Antonio/Tex.>
Fraunhofer ITEM ()
Chemical allergy; Regulatory policy; Respiratory sensitization; Nutrition

Public health and regulatory needs require approaches to detect and discriminate respiratory sensitizers from dermal sensitizers; however no single method or strategy is generally accepted. An Adverse Outcome Pathway (AOP) for respiratory tract sensitization by low molecular weight organic chemicals has been published and is proceeding through the Organization for Economic Cooperation and Development review process. This AOP is a useful foundation for the development and assessment of in vitro and in silico test methods and combinations thereof within one or more Integrated Approaches to Testing and Assessment (IATA). The published AOP identified several promising approaches; however most of these have only been assessed with a few well-known respiratory sensitizers (e.g., toluene diisocyanate or trimellitic anhydride). To further evaluate the utility of these and other approaches, 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 should cover a range of chemical classes and include “challenging” chemicals, 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, focusing on data verified in humans for translatability to human health outcomes. We are also making use of the Abstract Sifter literature review tool (Baker et al., (2007)) to identify additional potential respiratory sensitizers. Briefly, a set of PubMed MeSH terms describing adverse effects (AEs) for 92 known sensitizers was used to query a large database of chemicals and AEs, yielding over 7000 chemicals of potential interest. The top 500 ranked chemicals (based on article counts) are currently undergoing manual review. This reference chemical list is an important step towards the assessment of potential test methods and the creation of internationally-harmonized integrated approaches for the detection of chemical respiratory sensitizers. Does not necessarily represent US EPA policy.