title: Integrating toxicogenomics into human health risk assessment: lessons learned from the benzo[a]pyrene case study.
abstract: The use of short-term toxicogenomic tests to predict cancer (or other health effects) offers considerable advantages relative to traditional toxicity testing methods. The advantages include increased throughput, increased mechanistic data, and significantly reduced costs. However, precisely how toxicogenomics data can be used to support human health risk assessment (RA) is unclear. In a companion paper ( Moffat et al. 2014 ), we present a case study evaluating the utility of toxicogenomics in the RA of benzo[a]pyrene (BaP), a known human carcinogen. The case study is meant as a proof-of-principle exercise using a well-established mode of action (MOA) that impacts multiple tissues, which should provide a best case example. We found that toxicogenomics provided rich mechanistic data applicable to hazard identification, dose-response analysis, and quantitative RA of BaP. Based on this work, here we share some useful lessons for both research and RA, and outline our perspective on how toxicogenomics can benefit RA in the short- and long-term. Specifically, we focus on (1) obtaining biologically relevant data that are readily suitable for establishing an MOA for toxicants, (2) examining the human relevance of an MOA from animal testing, and (3) proposing appropriate quantitative values for RA. We describe our envisioned strategy on how toxicogenomics can become a tool in RA, especially when anchored to other short-term toxicity tests (apical endpoints) to increase confidence in the proposed MOA, and emphasize the need for additional studies on other MOAs to define the best practices in the application of toxicogenomics in RA.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada , Ottawa, ON , Canada.
authors.forename: Nikolai L
authors.initials: NL
authors.lastname: Chepelev
authors.forename: Ivy D
authors.initials: ID
authors.lastname: Moffat
authors.forename: Sarah
authors.initials: S
authors.lastname: Labib
authors.forename: Julie
authors.initials: J
authors.lastname: Bourdon-Lacombe
authors.forename: Byron
authors.initials: B
authors.lastname: Kuo
authors.forename: Julie K
authors.initials: JK
authors.lastname: Buick
authors.forename: France
authors.initials: F
authors.lastname: Lemieux
authors.forename: Amal I
authors.initials: AI
authors.lastname: Malik
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced; D018570:Risk Assessment / Q000379:methods*; D018675:Toxicity Tests; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D002273:Carcinogens; D001564:Benzo(a)pyrene
keywords: benchmark dose; carcinogens; dose–response; environmental pollutant; genotoxicity; mode of action; point of departure; polycyclic aromatic hydrocarbon