title: A chemical-biological similarity-based grouping of complex substances as a prototype approach for evaluating chemical alternatives.
abstract: Comparative assessment of potential human health impacts is a critical step in evaluating both chemical alternatives and existing products on the market. Most alternatives assessments are conducted on a chemical-by-chemical basis and it is seldom acknowledged that humans are exposed to complex products, not individual substances. Indeed, substances ofUnknown orVariable composition,Complex reaction products, andBiological materials (UVCBs) are ubiquitous in commerce yet they present a major challenge for registration and health assessments. Here, we present a comprehensive experimental and computational approach to categorize UVCBs according to global similarities in their bioactivity using a suite ofin vitromodels. We used petroleum substances, an important group of UVCBs which are grouped for regulatory approval and read-across primarily on physico-chemical properties and the manufacturing process, and only partially based on toxicity data, as a case study. We exposed induced pluripotent stem cell-derived cardiomyocytes and hepatocytes to DMSO-soluble extracts of 21 petroleum substances from five product groups. Concentration-response data from high-content imaging in cardiomyocytes and hepatocytes, as well as targeted high-throughput transcriptomic analysis of the hepatocytes, revealed distinct groups of petroleum substances. Data integration showed that bioactivity profiling affords clustering of petroleum substances in a manner similar to the manufacturing process-based categories. Moreover, we observed a high degree of correlation between bioactivity profiles and physico-chemical properties, as well as improved groupings when chemical and biological data were combined. Altogether, we demonstrate how novelin vitroscreening approaches can be effectively utilized in combination with physico-chemical characteristics to group complex substances and enable read-across. This approach allows for rapid and scientifically-informed evaluation of health impacts of both existing substances and their chemical alternatives.
authors.affiliation: Department of Veterinary Integrative Biosciences , Texas A&M University , College Station , TX , USA . Email: irusyn@cvm.tamu.edu ; ; Tel: +(979) 458-9866.
authors.forename: Fabian A
authors.initials: FA
authors.lastname: Grimm
authors.affiliation: Department of Veterinary Integrative Biosciences , Texas A&M University , College Station , TX , USA . Email: irusyn@cvm.tamu.edu ; ; Tel: +(979) 458-9866.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Molecular Devices LLC , Sunnyvale , CA , USA.
authors.forename: Oksana
authors.initials: O
authors.lastname: Sirenko
authors.affiliation: Department of Veterinary Integrative Biosciences , Texas A&M University , College Station , TX , USA . Email: irusyn@cvm.tamu.edu ; ; Tel: +(979) 458-9866.
authors.forename: Grace A
authors.initials: GA
authors.lastname: Chappell
authors.affiliation: Bioinformatics Research Center , North Carolina State University , Raleigh , NC , USA.
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: Bioinformatics Research Center , North Carolina State University , Raleigh , NC , USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
authors.affiliation: National Institutes of Health , National Center for Advancing Translational Sciences , Bethesda , MD , USA.
authors.forename: John
authors.initials: J
authors.lastname: Braisted
authors.affiliation: National Institutes of Health , National Center for Advancing Translational Sciences , Bethesda , MD , USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Gerhold
authors.affiliation: BioSpyder Technologies Inc. , Carlsbad , CA , USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Yeakley
authors.affiliation: BioSpyder Technologies Inc. , Carlsbad , CA , USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Shepard
authors.affiliation: BioSpyder Technologies Inc. , Carlsbad , CA , USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Seligmann
authors.affiliation: Department of Natural Science , University of South Carolina , Beaufort , SC , USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Roy
authors.affiliation: SHELL International BV , The Hague , NL , USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Boogaard
authors.affiliation: European Petroleum Refiners Association , Concawe Division , Brussels , BE , USA.
authors.forename: Hans B
authors.initials: HB
authors.lastname: Ketelslegers
authors.affiliation: ExxonMobil Chemical Co. , Spring , TX , USA.
authors.forename: Arlean M
authors.initials: AM
authors.lastname: Rohde
authors.affiliation: Department of Veterinary Integrative Biosciences , Texas A&M University , College Station , TX , USA . Email: irusyn@cvm.tamu.edu ; ; Tel: +(979) 458-9866.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn