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Crit Rev Toxicol. 2015 Jan;45(1):1-43. doi: 10.3109/10408444.2014.973934.

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.

Author information

1
Water and Air Quality Bureau, Health Canada, Ottawa, ON, Canada.
2
Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
3
National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
4
Drug Safety R&D, Pfizer Inc., Groton, CT, USA.
5
Biological Engineering Department, Utah State University, Logan, UT, USA.
6
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.
7
Integrated Laboratory Systems Inc., Research Triangle Park, NC, USA.
#
Contributed equally

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.

KEYWORDS:

benchmark dose; carcinogens; dose–response; environmental pollutant; genomics; human health risk assessment; mode of action; point of departure; polycyclic aromatic hydrocarbon; transcriptomics

PMID:
25605026
PMCID:
PMC4521608
DOI:
10.3109/10408444.2014.973934
[Indexed for MEDLINE]
Free PMC Article

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