title: Recommended approaches in the application of toxicogenomics to derive points of departure for chemical risk assessment.
abstract: There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health risk assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose-response studies on six chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in chemical risk assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for chemical risk assessment.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Farmahin
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Byron
authors.initials: B
authors.lastname: Kuo
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Nikolai L
authors.initials: NL
authors.lastname: Chepelev
authors.affiliation: National Center for Computational Toxicology, United States Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
authors.affiliation: Existing Substances Risk Assessment Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Tara S
authors.initials: TS
authors.lastname: Barton-Maclaren
authors.affiliation: Toxicology Research Division, Health Products and Food Branch, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Ivan H
authors.initials: IH
authors.lastname: Curran
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Andy
authors.initials: A
authors.lastname: Nong
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Wade
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada. carole.yauk@canada.ca.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
mesh_terms: D000818:Animals; D001969:Bromobenzenes / Q000008:administration & dosage / Q000633:toxicity; D002733:Chlorophenols / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D009602:Nitrosamines / Q000008:administration & dosage / Q000633:toxicity; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment / Q000379:methods*; D043922:Toxicogenetics / Q000379:methods*; D059467:Transcriptome
chemical_list: D001969:Bromobenzenes; D002733:Chlorophenols; D009602:Nitrosamines; C031487:2,3,4,6-tetrachlorophenol; C026924:1,2,4-tribromobenzene; C023649:N-nitrosodiphenylamine; C032036:bromobenzene
keywords: BMD; BMDL; LOAEL; Microarray; NOAEL; Point of departure; Risk assessment; Toxicogenomics; Transcriptomics