Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) / Chapter Skim
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8 Other Potential Applications of Toxicogenomic Technologies to Risk Assessment
8 Other Potential Applications of Toxicogenomic Technologies to Risk Assessment
Pages 121-134
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From page 121... ...
This chapter continues the discussion of toxicogenomic applications, focusing on several topics that are important to risk assessment: understanding dose-response relationships, especially at low doses, and improving the selection of doses used in testing; relating animal model data to human risk; assessing effects of exposure during development; and assessing the relevance of coexposures and the impact of mixtures. The implications that the increased use of toxicogenomics may have on experimental animal use and on federal agency infrastructure needs is also discussed.
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From page 122... ...
Because of their ability to detect more subtle changes at the molecular level than those detected by traditional high-dose animal studies, toxicogenomic studies, properly designed and interpreted, can provide greater insight into doseresponse relationships with respect to low-dose effects and mode of action (which affects the assumed shape of the dose-response relationship)
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From page 123... ...
Low doses resulted in damage to and regeneration of tubular epithelium, whereas high doses caused necrosis of tubular epithelium. Gene expression profiles clustered on the basis of similarities in the severity and type of pathology, and necrosis was associated with more changes in gene expression.
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From page 124... ...
. No-Effect Threshold Because conventional animal bioassays generally are conducted at high doses, risk assessors have particular interest in whether toxicogenomic technologies will provide empirical evidence of adverse effects at low doses.
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From page 125... ...
(2005a) found low doses of three estrogenic compounds that did not elicit transcriptional responses.
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From page 126... ...
These studies demonstrate that toxicogenomic technologies could be valuable in identifying animal models that most closely correspond to human toxicity and disease. Toxicogenomic technologies also offer the opportunity to explore the relevance to humans of toxicity findings that vary dramatically among model species.
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From page 127... ...
They also generated knock-in mice carrying the wild-type human PON1 or allelic variants that show enhanced susceptibility. This insertion of a variety of human xenobioticmetabolizing genes in mouse models and subsequent measurement of gene expression in response to chemical toxins should improve the ability to extrapolate from the laboratory to potential human exposures.
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From page 128... ...
The biologic significance of some of the genes and pathways affected, such as glycolysis genes crucial in maintaining oxygen levels, may provide insights into the mechanisms of teratogenesis. Toxicogenomic studies conducted to date have focused largely on iconic teratogens, exposing animals on a key gestational day and then attempting to identify gene changes that correlate with the teratogenic action observed.
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From page 129... ...
Although it is theoretically possible to obtain sufficient starting material (for example, mRNA) from a single cell, it is often not practical and sampling bias can easily arise because the "pooling" of multiple nonresponsive and noncritical target cells will diminish the signal-tonoise ratio (Kultima et al.
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From page 130... ...
Thus, future toxicogenomic studies examining the potential health effects of exposures to mixtures must address the confounding overlay of toxicogenomic signals associated with the range of substances present in diets and other environmental exposures. A critical element of this challenge is to determine how an exogenous exposure may truly be differentiated beyond the background pattern and variability of toxicogenomic expression associated with everyday "normal" activities such as dietary patterns, physical activities, disease status, and other lifestyle circumstances.
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From page 131... ...
For example, assumed health risks of environmental mixtures of dioxin-like compounds (for example, TCDD, tetrachlorodibenzofurans, polychlorinated biphenyls) are based on the central hypothesis that the individual toxicities of each of these compounds in a mixture can be cumulatively related to each other through a common mechanism of action involving activation of the AhR (EPA 1986; Safe 1990)
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From page 132... ...
IMPLICATIONS OF TOXICOGENOMICS FOR RISK ASSESSMENT INFRASTRUCTURE NEEDS A joint report developed by the Society of Toxicology and the Society of Environmental Toxicology and Chemistry pointed out that use of toxicogenomic information in risk assessment decision making will clearly be hindered if the parties ultimately responsible for decisions (regulatory agencies) do not have adequate resources and expertise to confidently analyze and interpret submitted data (Bus et al.
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From page 133... ...
To effectively address risk questions associated with human exposures to environmental chemicals, which may be much lower than doses currently used in toxicology studies, special attention must focus on characterizing toxicogenomic responses at low doses. Conducting toxicogenomic studies over a range of low doses may consume considerable laboratory, expertise, and financial resources.
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From page 134... ...
These results will afford valuable opportunities to extend knowledge of how to effectively translate animal model observations into credible estimates of potential human risk. If toxicogenomics can illustrate how currently known interspecies differences in toxicity can be more rapidly and clearly explained, it will offer the potential to significantly enhance the confidence in animal-to-human toxicity extrapolations that constitute a foundational element of risk evaluations.
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