title: Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water.
abstract: Toxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying toxicogenomics has never been done. We conducted a case study to evaluate the utility of toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in perturbed pathways with animal tissues. Quantitatively, the PODs for traditional and transcriptional approaches were similar (liver 1.2 vs. 1.0 mg/kg-bw/day; lungs 0.8 vs. 3.7 mg/kg-bw/day; forestomach 0.5 vs. 7.4 mg/kg-bw/day). RA3, which applied toxicogenomics in the absence of apical toxicology data, demonstrates that this approach provides useful information in data-poor situations. Overall, our study supports the use of toxicogenomics as a relatively fast and cost-effective tool for hazard identification, preliminary evaluation of potential carcinogens, and carcinogenic potency, in addition to identifying current limitations and practical questions for future work.
authors.affiliation: Water and Air Quality Bureau, Health Canada, Ottawa, ON, Canada.|Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Ivy
authors.initials: I
authors.lastname: Moffat
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Chepelev
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Labib
authors.affiliation: Water and Air Quality Bureau, Health Canada, Ottawa, ON, Canada.|Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Bourdon-Lacombe
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Byron
authors.initials: B
authors.lastname: Kuo
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Buick
authors.affiliation: Water and Air Quality Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: France
authors.initials: F
authors.lastname: Lemieux
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Sabina
authors.initials: S
authors.lastname: Halappanavar
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: Malik
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.affiliation: Drug Safety R&D, Pfizer Inc., Groton, CT, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.affiliation: Biological Engineering Department, Utah State University, Logan, UT, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Hyduke
authors.affiliation: Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.affiliation: Integrated Laboratory Systems Inc., Research Triangle Park, NC, USA.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Swartz
authors.affiliation: Integrated Laboratory Systems Inc., Research Triangle Park, NC, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Recio
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D060766:Drinking Water / Q000032:analysis; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics / Q000379:methods; D006801:Humans; D051379:Mice; D018570:Risk Assessment / Q000379:methods*; D013045:Species Specificity; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D002273:Carcinogens; D060766:Drinking Water; D001564:Benzo(a)pyrene
keywords: benchmark dose; carcinogens; dose–response; environmental pollutant; genomics; human health risk assessment; mode of action; point of departure; polycyclic aromatic hydrocarbon; transcriptomics