title: In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis.
abstract: Thousands of untested chemicals in the environment require efficient characterization of carcinogenic potential in humans. A proposed solution is rapid testing of chemicals using in vitro high-throughput screening (HTS) assays for targets in pathways linked to disease processes to build models for priority setting and further testing. We describe a model for predicting rodent carcinogenicity based on HTS data from 292 chemicals tested in 672 assays mapping to 455 genes. All data come from the EPA ToxCast project. The model was trained on a subset of 232 chemicals with in vivo rodent carcinogenicity data in the Toxicity Reference Database (ToxRefDB). Individual HTS assays strongly associated with rodent cancers in ToxRefDB were linked to genes, pathways, and hallmark processes documented to be involved in tumor biology and cancer progression. Rodent liver cancer endpoints were linked to well-documented pathways such as peroxisome proliferator-activated receptor signaling and TP53 and novel targets such as PDE5A and PLAUR. Cancer hallmark genes associated with rodent thyroid tumors were found to be linked to human thyroid tumors and autoimmune thyroid disease. A model was developed in which these genes/pathways function as hypothetical enhancers or promoters of rat thyroid tumors, acting secondary to the key initiating event of thyroid hormone disruption. A simple scoring function was generated to identify chemicals with significant in vitro evidence that was predictive of in vivo carcinogenicity in different rat tissues and organs. This scoring function was applied to an external test set of 33 compounds with carcinogenicity classifications from the EPA's Office of Pesticide Programs and successfully (p = 0.024) differentiated between chemicals classified as "possible"/"probable"/"likely" carcinogens and those designated as "not likely" or with "evidence of noncarcinogenicity." This model represents a chemical carcinogenicity prioritization tool supporting targeted testing and functional validation of cancer pathways.
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kleinstreuer
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Knudsen
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Martin
authors.forename: Katie B
authors.initials: KB
authors.lastname: Paul
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Crofton
authors.forename: Kerry
authors.initials: K
authors.lastname: Hamilton
authors.forename: Ronald
authors.initials: R
authors.lastname: Hunter
authors.forename: Imran
authors.initials: I
authors.lastname: Shah
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D016208:Databases, Factual; D023381:Endpoint Determination; D057166:High-Throughput Screening Assays; D066298:In Vitro Techniques; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics; D011237:Predictive Value of Tests; D051381:Rats; D013045:Species Specificity; D013964:Thyroid Neoplasms / Q000139:chemically induced / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D002273:Carcinogens