title: Integrative chemical-biological read-across approach for chemical hazard classification.
abstract: Traditional read-across approaches typically rely on the chemical similarity principle to predict chemical toxicity; however, the accuracy of such predictions is often inadequate due to the underlying complex mechanisms of toxicity. Here, we report on the development of a hazard classification and visualization method that draws upon both chemical structural similarity and comparisons of biological responses to chemicals measured in multiple short-term assays ("biological" similarity). The Chemical-Biological Read-Across (CBRA) approach infers each compound's toxicity from both chemical and biological analogues whose similarities are determined by the Tanimoto coefficient. Classification accuracy of CBRA was compared to that of classical RA and other methods using chemical descriptors alone or in combination with biological data. Different types of adverse effects (hepatotoxicity, hepatocarcinogenicity, mutagenicity, and acute lethality) were classified using several biological data types (gene expression profiling and cytotoxicity screening). CBRA-based hazard classification exhibited consistently high external classification accuracy and applicability to diverse chemicals. Transparency of the CBRA approach is aided by the use of radial plots that show the relative contribution of analogous chemical and biological neighbors. Identification of both chemical and biological features that give rise to the high accuracy of CBRA-based toxicity prediction facilitates mechanistic interpretation of the models.
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Yen
authors.initials: Y
authors.lastname: Low
authors.forename: Alexander
authors.initials: A
authors.lastname: Sedykh
authors.forename: Denis
authors.initials: D
authors.lastname: Fourches
authors.forename: Alexander
authors.initials: A
authors.lastname: Golbraikh
authors.forename: Maurice
authors.initials: M
authors.lastname: Whelan
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000633:toxicity; D000927:Anticonvulsants / Q000737:chemistry / Q000633:toxicity; D001419:Bacteria / Q000378:metabolism; D001553:Benzbromarone / Q000737:chemistry / Q000633:toxicity; D002220:Carbamazepine / Q000737:chemistry / Q000633:toxicity; D002701:Chloramphenicol / Q000737:chemistry / Q000633:toxicity; D062126:Databases, Chemical; D006074:Gout Suppressants / Q000737:chemistry / Q000633:toxicity; D015386:Hazardous Substances / Q000145:classification* / Q000633:toxicity; D008099:Liver / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D006074:Gout Suppressants; D015386:Hazardous Substances; D002220:Carbamazepine; D001553:Benzbromarone; D002701:Chloramphenicol