EXPANDED APPROACH FOR IDENTIFYING CANDIDATE ANALOGUE COMPOUNDS FOR READ ACROSS ASSESSEMENTS.
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To fill data-gaps and increase confidence in read-across assessments for data-poor compounds, an expanded analogue identification approach was developed. The Wang et al. (2012) read-across method is routinely applied to select analogues for screening-level assessment of compounds under the US EPA Peer Reviewed Provisional Toxicity Value (PPRTV) program. Under this method, an initial pool of analogues is identified by structural similarity using automated tools. We have built on this approach by expanding analogue searches, considering similarities in 1) structure, 2) metabolism and 3) mechanism of action. Step 1, additional structural features were identified by chemistry expertise to augment structural searches via automated tools. Step 2, searches for compounds with shared metabolism pathways were added to identify metabolites and metabolic precursors using experimental data and predictive tools. Step 3, searches for mechanistic analogues were conducted using tools such as GENRA, ToxCast/Tox21, and Comparative Toxicogenomics Database. This expanded approach is being applied to PPRTV compounds under evaluation for potential read-across. For example, four candidate analogues with inhalation toxicity values were identified for 1,3-dibromobenzene: bromobenzene (structural, shared metabolites), 1-bromo-3-fluorobenzene (structural), chlorobenzene (expert judgement), and 1,4-dichlorobenzene (expert judgement). Compounds identified via expert judgement had one benzene ring and 1–3 bromine and/or chlorine substituents. Two additional compounds (1,4¿dibromobenzene, 1,3¿dichlorobenzene) were identified that may fill data gaps with respect to the effects of halogen ring positioning (para vs. meta) and leaving groups (chlorine vs. bromine). For cis-1,2-dichloroethylene, this approach identified five candidate analogues: trans-1,2-dichloroethylene (structural, shared metabolites), vinyl chloride (structural), 1,1-dichloroethylene (shared metabolites), tetrachloroethylene (shared metabolites), trichloroethylene (shared metabolites). As demonstrated by these case studies, this expanded approach identified a more comprehensive set of candidate analogues to form the basis for read-across decisions. The views expressed are those of the authors and do not necessarily reflect the views and policies of the US EPA.