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.
Acknowledgements
We thank Amanda Green, Kim Shepard, and Phillip Garibaldi for technical support, and Paul White and Francesco Marchetti for helpful discussions. We thank Alexandra Long and Paul White for their insights into the metabolism of BaP and its ability to induce various genotoxic endpoints across multiple tissues and doses. We also thank the Water and Air Quality Bureau of Health Canada for its continued support in exploring new methodologies in risk assessment. We gratefully acknowledge the helpful comments and suggestions provided by Anne Vézina, Véronique Morisset, Lynn Berndt-Weis, Guosheng Chen, and Tara Barton-MacLaren, and the reviewers, unknown to the authors, who were assigned by the Journal's Editor.
Declaration of interest
The authors’ employment affiliations are as shown on the cover page. Health Canada and The Netherland's National Institute for Public Health and Environment are government agencies in their respective countries with broad missions for protecting and promoting public health. Pfizer is a public corporation engaged in the discovery, development, and manufacturer of a range of pharmaceuticals. Utah State University and Georgetown University are educational institutions that conduct research with public and private support. Integrated Laboratory Systems is a private company that conducts research for the U.S. government and private entities. The preparation of the paper was primarily supported by funding from the Health Canada Genomics Research and Development Initiative and the Canadian Regulatory Systems for Biotechnology. The individual authors were compensated by their employers. The conceptual basis for the paper, preparation of the paper, selection of the literature and its review, the conclusions drawn, and the recommendations made, were the professional work product of the authors and may not necessarily represent the views of Pfizer and Integrated Laboratory Systems.
Supplementary material available online
Supplementary Tables 1–7, Supplementary File A–C to be found online at http://informahealthcare.com/doi/abs/10.3109/10408444.2014.973934.