Genomics and Environmental Regulation: Science, Ethics, and Law

1 Toxicogenomics and Environmental Regulation

C H A P T E R 1 Toxicogenomics and Environmental Regulation GARY E. MARCHANT Toxicogenomics seeks to better understand toxic substances and their effects on living systems, with the ultimate objective of improving human health and environmental protection. This objective will in large part be accomplished through environmental regulation, and thus environmental regulation is an important context for the application of toxicogenomics. This chapter explores potential applications of toxicogenomic data in environmental regulation. For the purpose of this analysis, the primary focus will be on gene expression data, but many of the issues could also apply to other types of toxicogenomic data, such as proteomics and metabonomics . Toxicogenomic data have the potential to make environmental regulation more effective, efficient, and fair, but at the same time present many new evidentiary, policy, and ethical challenges. Regulatory Applications of Toxicogenomics Enhancing Regulatory Risk Assessment Major uncertainties and data gaps limit the utility and credibility of risk assessment for informing regulatory decisions (Latin, 1988; Horn- stein, 1992). These uncertainties include extrapolating results from animals to humans and from high-dose to more typical low-dose human exposures , understanding the mechanism of action of a toxicant and its implications for risk assessment, determining the shape of the doseresponse curve, and estimating the exposure levels for actual human populations (National Research Council, 1983). Gene expression data have the potential to help address many of these unknowns. Toxicogenomic data can improve risk assessment in several ways. First, gene expression data, by providing a characteristic “fingerprint” of different toxicological mechanisms, can be used to characterize the mechanism or mode of action of a toxicant (Aardema and MacGregor, 2002). Regulatory agencies such as the U.S. Environmental Protection Agency (EPA) have recently focused on mode of action as a key factor in risk assessment , because this information is critical for addressing the issues raised above and for deciding whether an agent is likely to exhibit a threshold below which there is no significant toxicity (Gallagher et al., 2006). As noted in EPA’s 2002 Interim Policy on Genomics, toxicogenomics will “likely provide a better understanding of the mechanism or mode of action of a stressor and thus assist in predictive toxicology, in the screening of stressors, and in the design of monitoring activities and exposure studies” (U.S. Environmental Protection Agency, 2002, p. 3). Second, gene expression data will be useful in extrapolating results obtained in animal and epidemiology studies that typically involve higher dose levels than those more relevant for the general human population . Until now, low-dose effects have generally been refractory to empirical analysis, and risk assessors have had to rely on models to extrapolate results from high to low dose levels. A finding that gene expression changes characteristic of the carcinogenic response of a particular agent at high doses are also observed in low-dose groups, even though those low-dose animals may not develop tumors, may indicate that lowdose exposures present a carcinogenic risk in large populations. Alternatively , the absence of any characteristic gene expression response in low-dose animals may suggest that the carcinogenic response occurs only at high doses (Farr and Dunn, 1999). Third, gene expression patterns may help to assess the relevance of animal studies for humans (Aardema and MacGregor, 2002). Most toxicology data comes from animal studies, which are often but not always relevant to humans. By providing a quick and inexpensive test of whether 12 E N V I R O N M E N T A L P O L I C Y P E R S P E C T I V E S a chemical is causing a similar response in rodents and humans, gene expression assays can help prevent false positives for chemicals that cause toxicity in rodents but not humans and false negatives for chemicals that cause toxicity in humans but not rodents. Fourth, gene expression data may also be beneficial for exposure assessment . Many types of environmental exposures lack adequate exposure data, which severely limits the ability to accurately determine the relationship between dose and response that underlies risk-assessment estimates. By characterizing gene expression patterns in exposed persons, microarrays have the potential to provide more precise quantitative estimates of exposure to specific toxic substances in contemporaneous and prospective human studies (Nuwaysir et al., 1999). Fifth, gene expression profiling may be particularly useful for evaluating the toxicity of chemical mixtures, which is difficult to...