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Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment

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Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment The new field of toxicogenomics presents a potentially powerful set of tools to better understand health effects from exposures to toxicants in the environment. However, realizing the potential of this nascent field to improve public health decisions will require a concerted effort 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. he Human Genome Project has been one of the most important Tbiological research projects of all time. The project produced a complete sequence of the chemical makeup of genetic information contained in the DNA in human cells. It also supported the development of many new “genomic technologies,” including research tools that allow scientists to look at 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 National combinations of genes lead to susceptibility to Institute of Environmental Health Sciences particular 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 the trial 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 in providing a more complete understanding of gene function that can be passed from parent to their potential toxic effects. Integrating such child. information into risk assessments could sig- Transcriptomics (or gene expression profiling) is the nificantly enhance public health and regula- study of mRNA—the intermediary step between genes tory 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 functions uses 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 to Toxicogenomics 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 shows of toxicogenomics, the challenges in achieving how exposures to chemicals cause cells in the body them, and potential approaches to overcoming the to turn on some genes and turn off others, which challenges. can change the proteins that are produced by the cell (see figure below for information on genes and Potential 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 calling nucleus of cells that code for cellular functions— card of the toxicant. Proteomics and metabolomics are essential to the development of the human body allow comparable analysis of protein and metabolite and 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 specific response to environmental agents or other factors toxicants, tracking cellular responses to different during a person’s lifetime. Such changes in gene ex- exposure levels, assessing the mechanisms by which pression can adversely affect bodily processes and toxicants cause diseases, and predicting variability cause illness. in individuals’ sensitivity to various toxicants. Traditional toxicology typically evaluates re- sponses such as death, disease causation, or micro- Use of Toxicogenomics in Risk Assessment scopic changes in the cells of animals and people. Toxicogenomics produces molecular-level data This report recommends that regulatory agen- about genes and how specific toxicants affect gene, cies enhance efforts to incorporate toxicogenomic protein, and metabolite patterns. Toxicogenom- data into risk assessment. However, these data are ics enables investigators to link toxicant-specific not currently ready to replace existing required molecular changes with responses in cells, tissues, testing regimens in risk assessment and regulatory and 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. Hazard Screening: Toxicogenomics mRNA 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 chemistry A 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 exposed to 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 one cogenomic technologies offer the potential to use of the primary tools genetic information to identify susceptible subpopu- of toxicogenom- lations and assess differences in susceptibility in ics. A microarray is a chip, based on larger populations. Toxicogenomics would then be those used by the able to inform regulatory processes to susceptibility electronics industry, within a population. that can “look” at Mechanistic Information: Toxicogenomics can thousands of human genes simultaneously. offer insight on the mechanisms by which chemi- Using microarrays, cal exposures cause diseases. Tools and approaches scientists can literally for elucidating the mechanisms involved in toxic re- see which genes are sponses should continue to be developed to enhance activated, repressed, risk assessment. or unchanged by a chemical. Cross-Species Extrapolation: Traditional toxicology makes 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 the lations by using human cells. Using toxicogenomics effect of each chemical in a mixture. It is unlikely to 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, but Dose-Response Relationships: Toxicogenomics has it should be possible to use mechanism-of-action the potential to improve understanding of dose-re- data to design toxicogenomic experiments to better sponse relationships—the understanding of how a inform this area of study. given level of exposure to a toxicant affects toxic responses in an individual. This understanding is The Need for a “Human Toxicogenomics particularly 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 widely known about the health impacts of fetal and early accepted by the scientific community and viewed as life exposures to many chemicals in current use. producing high-quality data. In order to realize the Because 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 other Box 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. Creation and management of a large, public database for storing and integrating the results of toxicoge- nomic analyses with conventional toxicity-testing data. 2. Assembly of toxicogenomic and conventional toxicological data on a large number (hundreds) of com- pounds into
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