Extending the Generalised Read-Across approach (GenRA): A systematic analysis of the impact of physicochemical property information on read-across performance.

Read-across is a useful data gap filling technique used within category and analogue approaches in regulatory hazard and risk assessment. Recently we developed an algorithmic, approach called Generalised Read-Across (GenRA) (Shah et al., 2016) which makes read-across predictions of toxicity effects using a similarity weighted average of source analogues characterised by their chemical and/or bioactivity descriptors. A default GenRA approach (termed baseline GenRA) relies on identifying 10 source analogues relative to a target substance that are structurally similar based on Morgan chemical fingerprints and computing an activity score to estimate presence or absence of in vivo toxicity. This current study investigated the impact that similarity in bioavailability plays in altering the local neighbourhood of source analogues as well as read-across performance relative to baseline GenRA using physicochemical property information as a surrogate for bioavailability. Two approaches were evaluated: 1) a filtering approach which restricted structurally related analogues based on their physicochemical properties; and 2) a search expansion approach which included additional analogues based on a combined structural and physicochemical similarity index. Filtering minimally improved performance, and was very dependent on the similarity threshold selected. The search expansion approach performed at least as well as the baseline GenRA, and showed up to a 9% improvement in read-across performance for at least 10 of the 50 organs considered. We summarise the overall impact that physicochemical information plays on GenRA performance, illustrate the improvement for a specific case study substance and describe how to select the most appropriate physicochemical similarity threshold to achieve optimal read-across performance depending on the toxicity effect and chemical of interest. The analyses show that physicochemical property information does result in a modest (up to 9% increase) improvement in structural based read-across predictions.