Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment The new field of toxicogenomics presents a potentially powerful set of tools to betterunderstand health effects from exposures to toxicants in the environment. However, realizingthe potential of this nascent field to improve public health decisions will require a concertedeffort to generate data, to make use of existing data, and to study data in new ways—an ef-fort requiring funding, interagency coordination, and data management strategies. T he Human Genome Project has been one of the most important biological research projects ofall time. The project produced a completesequence of the chemical makeup of geneticinformation contained in the DNA in humancells. It also supported the development ofmany new “genomic technologies,” includingresearch tools that allow scientists to lookat the complete set of genes in a single and legal concerns.experiment (see Box 1). These technologies This National Research Council re-allow scientists to study, for example, what port, produced at the request of the Nationalcombinations of genes lead to susceptibility to Institute of Environmental Health Sciencesparticular diseases, such as cancer. Now, scientists are applying genomic Box 1. Genomics refers to an array of methods to study genes and genomes, including:technologies to study the potentially adverse • gene sequencing, which applies various bio-effects of pharmaceutical drugs and indus- chemical and bioinformatics tools to study thetrial and environmental chemicals on human DNA of organisms.health. The new science of toxicogenomics • genotype analysis that looks at genetic varia-provides valuable information on the effects tion between individuals and in populations.of drugs and chemicals at a molecular level, • epigenetics that studies reversible changes inproviding a more complete understanding of gene function that can be passed from parent totheir potential toxic effects. Integrating such child.information into risk assessments could sig- Transcriptomics (or gene expression profiling) is thenificantly enhance public health and regula- study of mRNA—the intermediary step between genestory decisions. and proteins that indicates genes that are active (as op- However, leveraging the potential of posed to dormant or silent).toxicogenomics will require a coordinated Proteomics is the study of proteomes, which are col-effort to generate more data, make multiple lections of proteins. Proteins carry out the functionsuses of existing data sources, and study data encoded by genes.in new ways, perhaps on a scale approach- Metabolomics is the study of the products of biologi-ing that of the Human Genome Project. cal processes. Such products change in response toToxicogenomics also raises some ethical such things as nutrition, stress, and disease states.
(NIEHS), provides a broad overview of the benefits For example, gene expression profiling showsof toxicogenomics, the challenges in achieving how exposures to chemicals cause cells in the bodythem, and potential approaches to overcoming the to turn on some genes and turn off others, whichchallenges. can change the proteins that are produced by the cell (see figure below for information on genes andPotential to Enhance Toxicology proteins). The on-off pattern of the many genes in cells varies for different chemicals, creating a char- Genes—sections of a person’s DNA in the acteristic pattern or “signature”—the genetic callingnucleus of cells that code for cellular functions— card of the toxicant. Proteomics and metabolomicsare essential to the development of the human body allow comparable analysis of protein and metaboliteand the maintenance of bodily processes through- changes.out life. Not all genes are “expressed,” or actively Potential applications of toxicogenomics in-involved in a cellular function, at all times. Instead, clude improved methods for screening potential tox-genes may be “turned on” and “turned off” in icants, monitoring individuals’ exposures to specificresponse to environmental agents or other factors toxicants, tracking cellular responses to differentduring a person’s lifetime. Such changes in gene ex- exposure levels, assessing the mechanisms by whichpression can adversely affect bodily processes and toxicants cause diseases, and predicting variabilitycause illness. in individuals’ sensitivity to various toxicants. Traditional toxicology typically evaluates re-sponses such as death, disease causation, or micro-scopic changes in the cells of animals and people. Use of Toxicogenomics in Risk AssessmentToxicogenomics produces molecular-level data This report recommends that regulatory agen-about genes and how specific toxicants affect gene, cies enhance efforts to incorporate toxicogenomicprotein, and metabolite patterns. Toxicogenom- data into risk assessment. However, these data areics enables investigators to link toxicant-specific not currently ready to replace existing requiredmolecular changes with responses in cells, tissues, testing regimens in risk assessment and regulatoryand organisms. toxicology. The report recommends that toxi- cogenomic technologies be further developed to increase capabilities in the following areas: Exposure Assessment: Toxicogenom- ics should be developed further to identify genetic patterns associated with exposure to individual chemicals and, perhaps, to chemical mixtures. Standardized methods for identifying these signatures will be needed. NA Hazard Screening: Toxicogenomics mR should be developed further to en- able rapid screening of the potential toxicity of chemicals for drug devel- opment purposes and for determining the toxicity of chemicals found in the environment. Upon validation and de- velopment of adequate databases, tox- icogenomic screening methods should be integrated into relevant chemistryA genome is all of the DNA in an organism. Genes contained within this DNA regulatory and safety programs.code for proteins, which perform cellular functions. When a person is exposedto chemicals, cells in the body respond by switching on some genes and Variability in Susceptibility: Suscep-switching off others, thus changing the proteins that are produced by the cell. tibility to toxic effects of chemical
exposures varies from person to person. Toxi- Microarrays are onecogenomic technologies offer the potential to use of the primary toolsgenetic information to identify susceptible subpopu- of toxicogenom-lations and assess differences in susceptibility in ics. A microarray is a chip, based onlarger populations. Toxicogenomics would then be those used by theable to inform regulatory processes to susceptibility electronics industry,within a population. that can “look” at thousands of humanMechanistic Information: Toxicogenomics can genes simultaneously.offer insight on the mechanisms by which chemi- Using microarrays,cal exposures cause diseases. Tools and approaches scientists can literallyfor elucidating the mechanisms involved in toxic re- see which genes aresponses should continue to be developed to enhance activated, repressed,risk assessment. or unchanged by a chemical.Cross-Species Extrapolation: Traditional toxicologymakes use of animal studies, but animal-to-human possible to date about the potential effects of expo-toxicity extrapolations introduce uncertainty into risk sure to toxic substances in early development.assessment. Toxicogenomics offers the potential to Mixtures: Humans are frequently exposed to mul-significantly enhance the confidence of such extrapo- tiple chemicals, and it is difficult to determine thelations by using human cells. Using toxicogenomics effect of each chemical in a mixture. It is unlikelyto analyze species differences in toxicity will help ex- that toxicogenomic signatures will be able to deci-plain some of the molecular bases for such differences. pher all interactions among complex mixtures, butDose-Response Relationships: Toxicogenomics has it should be possible to use mechanism-of-actionthe potential to improve understanding of dose-re- data to design toxicogenomic experiments to bettersponse relationships—the understanding of how a inform this area of study.given level of exposure to a toxicant affects toxicresponses in an individual. This understanding is The Need for a “Human Toxicogenomicsparticularly useful for evaluating the effects of low Initiative”levels of exposure. The report notes that toxicogenomic technolo-Developmental Exposures: Relatively little is gies have matured to the point where they are widelyknown about the health impacts of fetal and early accepted by the scientific community and viewed aslife exposures to many chemicals in current use. producing high-quality data. In order to realize theBecause of their sensitivity, toxicogenomic tech- full potential of toxicogenomic technologies, how-nologies are expected to reveal more than has been ever, the report recommends that NIEHS and otherBox 2. Human Toxicogenomics Initiative (HTGI) The report recommends that NIEHS cooperate with other stakeholders in exploring the feasibility and objec-tives of a “Human Toxicogenomics Initiative” (HTGI). The initiative should include:1. reation and management of a large, public database for storing and integrating the results of toxicoge- C nomic analyses with conventional toxicity-testing data.2. ssembly of toxicogenomic and conventional toxicological data on a large number (hundreds) of com- A pounds into a single database. This includes the generation of new toxicogenomic data from humans and animals for a number of compounds on which other types of data already exist, as well as the consolida- tion of existing data.3. reation of a national biorepository for storing human clinical and epidemiological samples. C4. urther development of bioinformatics tools (e.g., software, analysis, and statistical tools). F5. onsideration of the ethical, legal, and social implications of collecting and using toxicogenomic data and C samples.6. oordinated subinitiatives to evaluate the application of toxicogenomic technologies to the assessment of C risks associated with chemical exposures.