This is a repository copy of Molecular fingerprint-derived similarity measures for toxicological read-across: Recommendations for optimal use.

A plethora of databases exist online that can assist in in silico chemical or drug safety assessment. However, a systematic review and grouping of databases, based on purpose and information content, consolidated in a single source, has been lacking. To resolve this issue, this review provides a comprehensive listing of the key in silico data resources relevant to: chemical identity and properties, drug action, toxicology (including nano-material toxicity), exposure, omics, pathways, Absorption, Distribution, Metabolism and Elimination (ADME) properties, clinical trials, pharmacovigilance, patents-related databases, biological (genes, enzymes, proteins, other macromolecules etc.) databases, protein-protein interactions (PPIs), environmental exposure related, and finally databases relating to animal alternatives in support of 3Rs policies. More than nine hundred databases were identified and reviewed against criteria relating to accessibility, data coverage, interoperability or application programming interface (API), appropriate identifiers, types of in vitro, in vivo ,-clinical or other data recorded and suitability for modelling, read-across, or similarity searching. This review also specifically addresses the need for solutions for mapping and integration of databases into a common platform for better translatability of preclinical data to clinical data.

The ability of the liver to simultaneously carry out multiple functions is dependent on the metabolic heterogeneity of hepatocytes spatially located within a liver lobule spanning from the portal triad to the central vein. This complex zonal architecture of the liver, however, makes accurate in vitro modeling a challenge and often standard culture systems assume a homogenous model which may lead to inaccurate translatability of results. Here, we use a combination of mathematical modeling and experimental data to demonstrate a readily constructible in vitro flow system capable of liver zonation in primary rat hepatocytes. We show the differential expression of zonation markers, enhanced functionality when compared to standard static cultures and zone-specific metabolism and cell damage in the presence of paracetamol, a known zone-specific toxin. This type of advanced system provides a more in-depth and essential understanding of liver physiology and pathophysiology as well as the accurate evaluation of pharmacological interventions at a zone-specific level.

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