Approaches to advancing quantitative human health risk assessment of environmental chemicals in the post-genomic era ☆ Weihsueh A. Chiu ⁎, Susan Y. Euling, Cheryl Siegel Scott, Ravi P. Subramaniam National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington DC, 20460, USA abstract article info Article history: Received 19 January 2010 Revised 19 March 2010 Accepted 22 March 2010 Available online 28 March 2010 Keywords: Toxicogenomics Biomarkers Molecular epidemiology Risk assessment Dose–response assessment The contribution of genomics and associated technologies to human health risk assessment for environmental chemicals has focused largely on elucidating mechanisms of toxicity, as discussed in other articles in this issue. However, there is interest in moving beyond hazard characterization to making more direct impacts on quantitative risk assessment (QRA) — i.e., the determination of toxicity values for setting exposure standards and cleanup values. We propose that the evolution of QRA of environmental chemicals in the post-genomic era will involve three, somewhat overlapping phases in which different types of approaches begin to mature. The initial focus (in Phase I) has been and continues to be on “augmentation” of weight of evidence — using genomic and related technologies qualitatively to increase the confidence in and scientific basis of the results of QRA. Efforts aimed towards “integration” of these data with traditional animal-based approaches, in particular quantitative predictors, or surrogates, for the in vivo toxicity data to which they have been anchored are just beginning to be explored now (in Phase II). In parallel, there is a recognized need for “expansion” of the use of established biomarkers of susceptibility or risk of human diseases and disorders for QRA, particularly for addressing the issues of cumulative assessment and population risk. Ultimately (in Phase III), substantial further advances could be realized by the development of novel molecular and pathway-based biomarkers and statistical and in silico models that build on anticipated progress in understanding the pathways of human diseases and disorders. Such efforts would facilitate a gradual “reorientation” of QRA towards approaches that more directly link environmental exposures to human outcomes. Published by Elsevier Inc. Introduction The decade since the term “toxicogenomics” was first coined in 1999 (Nuwaysir et al., 1999) has seen an explosion in the use of genomic and other high-throughput/high content (HT/HC) technol- ogies in toxicology and throughout biology. This growth has been driven to a great extent by pharmaceutical applications, such as “pharmacogenomics,” where screening and prioritization are among the primary uses (Gant, 2007; Ikediobi et al., 2009). Indeed, several current initiatives in human health risk assessment for environmental chemicals, such as the ToxCast™ effort (Dix et al., 2007), are drawing on experiences from and developing approaches for screening and/or prioritization. While these are likely to yield useful tools in the future, the impact thus far of the new data and technologies available in this “post-genomic era” on human health risk assessment of environmen- tal chemicals — comprised of hazard identification, dose–response assessment, exposure assessment, and risk characterization — has as yet been limited. Moreover, visions of the future use of genomic and other HT/HC data in human health risk assessment of environ- mental chemicals range widely, from incremental (e.g., Cohen, 2004) to the far-reaching (e.g., NRC, 2007b; Collins et al., 2008), depending in part on whether nearer- or longer-term applications are being discussed. In addition, there is great interest in considering how these new data and technologies may impact dose–response assessment. To avoid confusion with “dose–response” in the context of data analysis, rather than in the context of human health risk assessment for environmental chemicals, the term “quantitative risk assessment” Toxicology and Applied Pharmacology 271 (2013) 309–323 Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry; BMD, benchmark dose; DPX, DNA–protein crosslinks; EPA, Environmental Protection Agency; GO, gene ontology; GST, glutathione-S-transferase; HT/HC, high throughput/high content; HuGE, Human Genome Epidemiology; IRIS, Integrate Risk Information System; IQ, intelligence quotient; LOAEL, lowest observed adverse effect level; MOA, mode of action; NCCT, National Center for Computational Toxicology; NOAEL, no observed adverse effect level; NOTEL, no observed transcriptional effect level; NRC, National Research Council; POD, point of departure; QRA, quantitative risk assessment; RfC, reference concentration; RfD, reference dose. ☆ This manuscript has been reviewed by the U.S. Environmental Protection Agency and approved for publication. The views expressed in this manuscript are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. ⁎ Corresponding author. U.S. Environmental Protection Agency — 8623P, Two Potomac Yard (North Building), 2733 South Crystal Drive, Arlington, VA 22202, USA. Fax: +1 703 347 8692. E-mail address: chiu.weihsueh@epa.gov (W.A. Chiu). 0041-008X/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.taap.2010.03.019 Contents lists available at ScienceDirect Toxicology and Applied Pharmacology journal homepage: www.elsevier.com/locate/ytaap