Toxicogenomic profiling of chemically exposed humans in risk assessment

Abstract

Gene-environment interactions contribute to complex disease development. The environmental contribution, in particular low-level and prevalent environmental exposures, may constitute much of the risk and contribute substantially to disease. Systematic risk evaluation of the majority of human chemical exposures, has not been conducted and is a goal of regulatory agencies in the U.S. and worldwide. With the recent recognition that toxicological approaches more predictive of effects in humans are required for risk assessment, in vitro human cell line data as well as animal data are being used to identify toxicity mechanisms that can be translated into biomarkers relevant to human exposure studies. In this review, we discuss how data from toxicogenomic studies of exposed human populations can inform risk assessment, by generating biomarkers of exposure, early effect, and/or susceptibility, elucidating mechanisms of action underlying exposure-related disease, and detecting response at low doses. Good experimental design incorporating precise, individual exposure measurements, phenotypic anchors (pre-disease or traditional toxicological markers), and a range of relevant exposure levels, is necessary. Further, toxicogenomic studies need to be designed with sufficient power to detect true effects of the exposure. As more studies are performed and incorporated into databases such as the Comparative Toxicogenomics Database (CTD) and Chemical Effects in Biological Systems (CEBS), data can be mined for classification of newly tested chemicals (hazard identification), and, for investigating the dose-response, and inter-relationship among genes, environment and disease in a systems biology approach (risk characterization).

Figure 1. Application of Human Toxicogenomic Studies to Risk Assessment

The application of the OMIC technologies to human health risk assessment is shown. Adductomics, transcriptomics, proteomics, and epigenomics can each provide a “molecular signature” or “fingerprint” of exposure or early effect (hazard identification) which may enhance our understanding of the mechanisms by which these chemicals cause toxicity and contribute to disease (risk characterization), at a range of environmentally relevant exposure levels (dose response). These omic signatures and ultimately, risk, induced by exposure, are determined by the unique genomic composition of each individual and biomarkers of susceptibility can be determined through genomic analyses. Thus, adductomics, transcriptomics, proteomics, and epigenomics can characterize the exposome, responsome and (early) outcome of each individual in the context of underlying susceptibility (genomics), facilitating the examination of gene-environment interactions. Correlation of toxicogenomic data with phenotypic endpoints, such as traditional toxicological or clinical endpoints or pre-disease states (phenotypic anchors), could help to predict outcome greatly improving the rigorous application of this approach to risk assessment.