Genomics and Environmental Regulation: Science, Ethics, and Law

3 Application of Genomics for Health and Environmental Safety of Chemicals: An Industry Perspective

C H A P T E R 3 Application of Genomics for Health and Environmental Safety of Chemicals An Industry Perspective RICHARD D. PHILLIPS The advent of genomic technologies has facilitated major advances in our understanding of the molecular details of normal biology and holds the promise of providing new insights into molecular mechanisms of a variety of toxicities. These “-omics“ technologies provide many potential benefits for assessment of chemical safety. Among the more promising areas are opportunities for more effective screening and priority setting for chemicals. In addition, it is possible to identify biomarkers of chemical exposure at the molecular level and potential interactions of chemicals and effects at low doses. Genomics will likely lead to an improved understanding of mechanisms of action, thereby reducing uncertainty and improving chemical risk assessments, and of the use and limitations of toxicological models. This will enable the application of computational toxicology models in risk assessment. Finally, it will be possible to identify and quantify susceptible populations for protection in unique instances as appropriate. Although we anticipate the many important applications listed above, much is still to be done in developing and applying of these technolo- gies before we realize their full benefit. As the technologies develop, we’ll need to proceed with caution to avoid overinterpretation and inefficiency, which could delay progress. A rigorous and disciplined scientific approach will be needed to realize the benefits as quickly as possible. Henry et al. (2002) reported the outcome of a multiple-stakeholder workshop that considered the issues regarding the application of genomic technologies to toxicology and epidemiology. The workshop identified challenges, opportunities, and possible areas for high value research. Among the global challenges was the enormous volume of information generated and how that information should be managed and assimilated in a productive manner. In addition, the need for standardized methods and platforms was seen as critical. Cunningham and colleagues (2003) observed that the barriers to the broad application of “-omics” include the lack of publicly available databases, the paucity of validated technologies, and the lack of comparative data on experimental platforms, experimental approaches , and study design. Other challenges include the immaturity of robust tools for data analysis and uncertainty about the direct relationship between transcripts and toxicity and about regulatory applications. Yet another major challenge that needs to be addressed is the method of analyzing complex data sets that require sophisticated bioinformatics to unravel how small changes in gene expression relate to disease development. This level of analysis then needs to be linked, both qualitatively and quantitatively , to the association between gene and protein changes following exposure to chemicals and the ultimate outcome of disease. Other potential obstacles include the high cost of replicate measures and collection of the data as dichotomous variables (e.g., the gene expression level exceeds a predefined threshold or it does not). Also, there is the difficult task of integrating the vast amount of data into meaningful patterns overlaid on top of background fluctuations in cell cycle, diurnal cycles, developmental maturation, and aging. Understanding complex diseases has challenges as well. Large population case control studies may well detect some individual genetic determinants associated with moderate relative risks of specific diseases. However, these genetic determinants may not act independently. Understanding the combined quantitative contributions of alleles at many speci fic loci to polygenic traits, and interactions among loci, will require overcoming substantial multiple comparison problems in studies in which effects at thousands of loci are investigated. 36 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 Notwithstanding these challenges, several key opportunities presented by genomic technologies were identified by Henry et al. (2002), among them, improved understanding of mechanism or mode of action of chemical interaction with biological systems. This will ultimately lead to improved risk assessments by reducing key uncertainties such as doseresponse relationships leading to adverse or toxic effects, threshold responses , and the relationship of responses in surrogate species to target species. This type of information will improve our understanding of mode of action and the biologic plausibility of exposure-effect relationships. Identification of biomarkers of chemical exposure and effects is another important need for improving risk assessment. “-Omics” tools should inform the search for useful biomarkers of effect and exposure and better characterize...