Application of Toxicogenomics to Cross-Species Extrapolation A Report of a Workshop (2006) / Chapter Skim
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Summary of Workshop
Summary of Workshop
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Although experimental animal data often constitute the only available predictor of human health effects, their predictive ability is limited. There are numerous differences between experimental animal and human responses to chemicals, including differences in the types of adverse effects experienced and the dosages at which they occur.
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The National Academies standing Committee on Emerging Issues and Data on Environmental Contaminants, sponsored by the National Institute of Environmental Health Sciences, provides a forum for communication among scientists and regulators in government, industry, environmental groups, the academic community, and the general public about topics at the forefront of toxicogenomics. The objective of the workshop reported here was to explore some of the scientific challenges and promises of applying toxicogenomic information to the extrapolation of animal data to humans.
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Leigh Anderson, of the Plasma Proteome Institute, chair of the Application of Toxicogenomics to Cross-Species Extrapolation workshop planning committee, introduced the topic of cross-species extrapolation and explained the objectives of the workshop. The potential uses of toxicogenomic technologies in cross-species extrapolation were the topics of discussion.
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To function in this way, in vitro systems need to replicate sufficiently the in vivo characteristics of interest in the test species and in humans. EMERGING MOLECULAR AND COMPUTATIONAL APPROACHES FOR CROSS-SPECIES EXTRAPOLATION Richard Di Giulio, of Duke University, presented highlights of a 2002 report he and William H
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POTENTIAL IMPLICATIONS OF GENOMICS FOR RISK ASSESSMENT Benson discussed potential implications of genomics for regulatory and risk assessment applications at EPA, focusing largely on a white paper on genomics and risk assessment that EPA released in March 2004 (Dearfield and Benson 2004; EPA 2004)
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. The general objectives of the program are to improve the linkages in the source-to-outcome continuum, provide predictive models for screening and testing chemicals, and enhance quantitative risk assessment.
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Bus, of the Dow Chemical Company, and Di Giulio discussed how there are long-term opportunities to improve risk assessment, perhaps through different paradigms. Di Giulio's statement, that -omics will not replace traditional toxicologic approaches sparked discussion.
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TECHNOLOGICAL CHALLENGES OF CROSS-SPECIES EXTRAPOLATION USING PROTEOMICS Frank A Witzmann, of Indiana University, discussed technological challenges of cross-species extrapolation using proteomics.
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Witzmann was asked about the commonalities between the in vitro rat proteome and the human proteome. He said that "the 2D protein patterns seem very similar, but these expression profiles need to be analyzed more comprehensively and in a coherently designed way." MODELING GENE-EXPRESSION DATA TO PREDICT HUMAN HEPATOTOXICITY AFTER INCONSISTENT ANIMAL RESPONSES Donna Mendrick, of Gene Logic, outlined how her company has used toxicogenomic approaches to analyze the relevance of some tradi
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. To determine whether these canine genes might be relevant to human fibrosis, Gene Logic's BioExpress database of normal and diseased human tissue samples was used to compare genes dysregulated in the dog liver with genes dysregulated in humans who had liver fibrosis.
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In summary, looking at the whole of what was learned with the phenobarbital comparisons and the liver fibrosis difference in humans, Mendrick concluded that the data might suggest that the gene dysregulation in the dog did not predict human health liabilities and that compound X might warrant further investigation. She pointed out that it would be useful to consider how much detail is needed to explain species differences; that is, what is sufficient to "make the case." USING METABOLOMICS TO EXPLORE SPECIES DIFFERENCES IN METABOLISM AND DISTRIBUTION Susan Sumner, of Paradigm Genetics,3 discussed metabolism, metabolomics, and cross-species extrapolation.
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We already know that chemicals can interact with endogenous compounds (for example, by forming conjugates with glutathione) , so we can expect introduction of a chemical to result in alteration of the endogenous metabolite profiles.
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The metabolites making up the specific profiles associated, for example, with a disease state can then be mapped to metabolic pathways for mechanistic association. However, mapping to metabolic pathways is not always straightforward, because a given metabolite can map to a number of pathways, and the specific pathways affected are not always known.
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A SYSTEMS-BIOLOGY APPROACH TO CROSS-SPECIES EXTRAPOLATION Russell Thomas, of the CIIT Centers for Health Research, discussed a systems-biology approach to cross-species extrapolation. To introduce why he believes that a systems approach is important for mechanism-based risk assessment, Thomas outlined two fundamental ways of determining how species can differ in their responses to a toxic 4After the workshop, a study was published on the feasibility of using metabolomics in clinical studies without dietary restrictions.
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In addressing the first of the four steps, Thomas described the application of large-scale gain-of-function and loss-of-function genomic screens to identify genes that play a functional role in a given pathway and may also represent potential targets of perturbation by a toxic agent. Cell-based assays are constructed by engineering cells to express a fluorescent or luminescent reporter gene when a specific signaling pathway is activated.
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The RNAi treatment blocks the function of the regulatory gene and identifies dependent downstream changes in gene expression. By linking key regulatory genes at early points with secondary or tertiary gene-expression changes, the approach identifies how different signaling pathways interconnect to form a network.
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, so the task is not insurmountable. COMBINING TRANSCRIPTIONAL AND TOXICOLOGIC APPROACHES TO UNDERSTANDING THE BASIS OF SPECIES DIFFERENCES IN CONAZOLE CARCINOGENESIS Stephen Nesnow, of EPA, described work being done at the National Health and Environmental Effects Research Laboratory in combin
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Nesnow and colleagues used traditional toxicologic methods combined with transcriptomics to study the MOA of carcinogenic conazoles and examine the toxicologic differences between rats, mice, and humans with the goal of determining whether modulation of P450 was the common underlying toxicologic event. They selected thyroid cancer in rats and liver cancer in mice as the end points of interest and studied a series of carcinogenic and noncarcinogenic conazoles.
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Most of the analyzed data instead are on traditional toxicologic measures (liver weight, P450 activity, and so on) for the different conazoles.
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during the first 5 postnatal days. In a further study of adult male and pregnant female mice and rats given PFOA through gestation, male mice and rats had statistically higher serum PFOA concentrations than females, and both sexes of mice TABLE 1 Species- and Sex-Related Differences in PFOA Elimination Half-Life Half-Life Species Males Females Mouse 12 days 20 days Rat 4-6 days 2-4 hours Rabbit 5.5 hours 7.0 hours Dog 20-30 days 8-13 days Monkey About 21 days About 30 days Human (retired 3M workers)
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-Omics technologies may be useful for exploring protein expression as a basis of sex, species, and age differences in PFOA elimination and ultimately for informing risk assessment of this chemical. One group in Japan is already exploring the basis of sex differences in rats by looking at the mRNA expression of various OAT forms after castration or ovariectomy (Kudo et al.
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In its risk assessments, however, EPA also describes other possible MOAs, and these may add to the weight of evidence for the hazard assessment. In the past, EPA used just one effect as the end point for its hazard assessment, but it recognizes that with the advent of the -omic technologies there may be many cellular activities that affect a 6Dearfield is now with the U.S.
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For example, rather than seeing whether dysregulated genes are conserved across species, it is important to look at the pathway that the dysregulated genes suggest may be involved and ask whether similar pathways exist and are dysregulated in humans. Sumner discussed the importance of mapping metabolites of interest to metabolic pathways and comparing the pathways across species.
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In response to the discussion about how toxicology can move beyond testing chemicals at high dosages to determining effects at actual, low dosages, Mendrick asked how scientists could determine which changes at a low dosage, that do not result in overt traditional pathologic effects, signal impending toxicity. She described Gene Logic's doseescalation approach.
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Furthermore, some uncertainty factors depend on statutes, such as the Food Quality Protection Act, because they define what is legally considered safe. Dearfield asked some pragmatic questions faced by risk assessors who extrapolate from animal data to human health.
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Should a different uncertainty factor be applied for interspecies extrapolation if genomics data reveal that some pathway or metabolite is well conserved in humans? Although EPA does not have answers for those questions, it is starting to explore the use of toxicogenomics to better characterize such variability and to refine the use of uncertainty factors.
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Eaton agreed that even without an understanding of mechanisms, toxicogenomic tools may be useful as screening tools for priority setting, either among potential pharmaceutical leads in the drug world, or, at EPA, among new chemicals to test. That application of the technologies would not necessarily replace traditional toxicologic evaluation aimed at understanding mechanisms, but it is important not to sell the technologies short for their potential screening application.
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That is, to apply traditional toxicologic measures to end points or biologic processes that -omics data suggest may be important. Sumner supported using -omics data as a signal of pathologic outcome but also for integrating them with traditional toxicology approaches, such as the use of the area under the curve and physiologically based pharmacokinetic modeling.
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Such research will highlight similarities or dissimilarities of biochemical pathways and mechanisms between test species and humans.
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2004. Genomics implications for EPA regulatory and risk assessment applications.
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2004. Potential Implications of Genomics for Regulatory and Risk Assessment Applications at EPA.
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32 Application of Toxicogenomics to Cross-Species Extrapolation pathophysiological stimuli via multivariate statistical analysis of biologic NMR spectroscopic data. Xenobiotica 29(11)
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