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.

Keywords:

• benchmark dose
• carcinogens
• dose–response
• environmental pollutant
• genotoxicity
• mode of action
• point of departure
• polycyclic aromatic hydrocarbon

Acknowledgments

We thank Amanda Green, Kim Shepard, and Phillip Garibaldi for technical support; 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 RA. 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 in 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 manufacture 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.