title: Impact of Genomics Platform and Statistical Filtering on Transcriptional Benchmark Doses (BMD) and Multiple Approaches for Selection of Chemical Point of Departure (PoD).
abstract: Many regulatory agencies are exploring ways to integrate toxicogenomic data into their chemical risk assessments. The major challenge lies in determining how to distill the complex data produced by high-content, multi-dose gene expression studies into quantitative information. It has been proposed that benchmark dose (BMD) values derived from toxicogenomics data be used as point of departure (PoD) values in chemical risk assessments. However, there is limited information regarding which genomics platforms are most suitable and how to select appropriate PoD values. In this study, we compared BMD values modeled from RNA sequencing-, microarray-, and qPCR-derived gene expression data from a single study, and explored multiple approaches for selecting a single PoD from these data. The strategies evaluated include several that do not require prior mechanistic knowledge of the compound for selection of the PoD, thus providing approaches for assessing data-poor chemicals. We used RNA extracted from the livers of female mice exposed to non-carcinogenic (0, 2 mg/kg/day, mkd) and carcinogenic (4, 8 mkd) doses of furan for 21 days. We show that transcriptional BMD values were consistent across technologies and highly predictive of the two-year cancer bioassay-based PoD. We also demonstrate that filtering data based on statistically significant changes in gene expression prior to BMD modeling creates more conservative BMD values. Taken together, this case study on mice exposed to furan demonstrates that high-content toxicogenomics studies produce robust data for BMD modelling that are minimally affected by inter-technology variability and highly predictive of cancer-based PoD doses.
authors: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada; Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Canada.
authors: A Francina
authors: AF
authors: Webster
authors: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors: Nikolai
authors: N
authors: Chepelev
authors: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors: Rémi
authors: R
authors: Gagné
authors: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors: Byron
authors: B
authors: Kuo
authors: Integrated Laboratory Systems Inc., Research Triangle Park, North Carolina, United States of America.
authors: Leslie
authors: L
authors: Recio
authors: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors: Andrew
authors: A
authors: Williams
authors: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors: Carole L
authors: CL
authors: Yauk
mesh_terms: D000818:Animals; D019985:Benchmarking; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000633:toxicity; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics / Q000379:methods / Q000706:statistics & numerical data*; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008815:Mice, Inbred Strains; D008962:Models, Theoretical; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D018570:Risk Assessment / Q000379:methods; D017423:Sequence Analysis, RNA / Q000379:methods; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D002273:Carcinogens; D005663:Furans; C039281:furan