Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) / Chapter Skim
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1 Introduction
1 Introduction
Pages 11-21
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From page 11... ...
The genomic knowledge and new technologies that have emerged in the post-genomic era promise to inform the understanding of many risks as well as enlighten current approaches and lead to novel predictive approaches for studying disease risk. As biologic knowledge progresses with the science of toxicology, "toxicogenomics" (see Box 1-1 for definition)
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From page 12... ...
These studies constitute the mainstays of toxicologic practice.3 In addition to animal studies, efforts to identify and understand the effects of environmental chemicals, drugs, and other agents on human populations have used epidemiologic studies to examine the relationship between a dose and the response to exposures. In contrast to animal studies, in which exposures are experimentally controlled, epidemiologic studies describe exposure with an estimate of error, and they assess the relationship between exposure and disease distribution in human populations.
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From page 13... ...
Current technology now enables the role of multiple genes of cell signaling pathways to be examined in human population studies aimed at assessing the interplay between environmental exposures and cancer risk. Although current practice in toxicology continues to strongly emphasize changes observable at the level of the whole organism as well as at the level of the organ, the use of cellular and molecular end points sets the stage for applying toxicogenomic technologies to a more robust examination of how complex molecular and cellular systems contribute to the expression of toxicity.
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From page 14... ...
Genomic technologies encompass both genome sequencing technologies, which derive DNA sequences from genes and other regions of DNA, and genotype analysis, which detects sequence variations between individuals in individual genes. Whereas the sequencing of genomes was once an extraordinary undertaking, rapid evolution of sequencing technology has dramatically increased throughput and decreased cost, now outperforming the benchmark technology standard used for the Human Genome Project.
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From page 15... ...
A key strength of metabolomic approaches is that they can be used to noninvasively and repeatedly measure changes in living tissues and living animals and that they measure changes in the actual metabolic flow. As with proteomics, the major limitation of metabolomics is the difficulty of comprehensively measuring diverse metabolites in complex biologic systems.
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From page 16... ...
strives to use environmental sciences to understand human disease and improve human health, including "how environmental exposures fundamentally alter human biology" and why some people develop disease in response to toxicant exposure and others do not.4 In sum, NIH, regulatory agencies, the chemical and pharmaceutical industries, health professionals, attorneys, the media, and the general public are all interested in knowing how new genomic technologies developed in the aftermath of the Human Genome Project can improve our understanding of toxicity and ultimately protect public health and the environment. Although the FDA and the EPA have developed planning documents on toxicogenomic policies (see Chapter 9)
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From page 17... ...
Peer-reviewed and published papers in the public domain were selected to illustrate applications the committee identified as worthy of consideration. For example, Box 1-4 contains brief summaries of selected studies where toxicogenomic technologies have shown promise in predictive toxicology.
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From page 18... ...
This study will provide a broad overview for the public, senior government policy makers, and other interested and involved parties of the benefits potentially arising from these technologies, identify the challenges to achieving them, and suggest approaches and incentives that may be used to address the challenges. Potential scientific benefits might include identifying susceptible popula tions and mechanisms of action and making better use of animal toxicity testing.
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From page 19... ...
BOX 1-4 Selected Examples of the Use of Toxicogenomic Technologies in Predictive Toxicology Predictive toxicology is predicated on the hypothesis that similar treatments leading to the same end point will share comparable changes in gene expression. Examples where toxicogenomic technologies have such shown promise in predic tive toxicology are presented below.
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From page 20... ...
The two signifi cant metabolic networks unveiled were shikimate and serine, threonine and gluta mate biosynthesis. Transcriptional profiling of specific deletion strains confirmed that the several transcription factors strongly mediate the cell's adaptation to arse nic-induced stress.
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From page 21... ...
. This overlap of sensitive upstream pathways and differentially expressed downstream pathways provides the link between transcriptional and phenotypic profiling data."
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