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4 Tools and Technologies
Pages 98-119

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From page 98...
... 4 Tools and Technologies In Chapter 2, the committee provided an overview of its vision for toxicity testing, and Chapter 3 described the main components of the vision. Here, tools and technologies that might be used to apply the committee's vision are briefly discussed.
From page 99...
... 99 Tools and Technologies ity, and metabolism of an agent of concern. All are conceptually based on the similar-property principle, that is, that chemicals with similar structure are likely to exhibit similar activity (Tong et al.
From page 100...
... 100 Toxicity Testing in the 21st Century relative programs (such as CASE/MultiCASE and TOPKAT) and rule-based expert systems (such as DEREK and ONCOLOGIC)
From page 101...
... 101 Tools and Technologies been incorporated into expert systems for predicting toxic effects of chemicals (Simon-Hettich et al.
From page 102...
... 102 Toxicity Testing in the 21st Century MAPPING TOXICITY PATHWAYS As discussed in Chapters 2 and 3, the key component of the committee's vision is the evaluation of perturbations in toxicity pathways. Many tools and technologies are available that can aid in the identification of biologic signaling pathways and the development of assays to evaluate their function.
From page 103...
... 103 Tools and Technologies In Vitro Tests The committee foresees that in vitro assays will make up the bulk of the toxicity tests in its vision. In vitro tests are currently used in traditional toxicity testing and indicate the success of developing and using in vitro assays (Goldberg and Hartung 2006)
From page 104...
... 104 Toxicity Testing in the 21st Century drug-metabolism studies (Potier et al.
From page 105...
... 105 Tools and Technologies (Lee and Dordick 2006)
From page 106...
... 106 Toxicity Testing in the 21st Century Microarrays are high-throughput analytic devices that provide comprehensive genome-scale expression analysis by simultaneously monitoring quantitative transcription of thousands of genes in parallel (Hoheisel 2006)
From page 107...
... Functional genomics should be distinguished from toxicogenomics. Toxico 1 genomics is a broad field combining expertise in toxicology, genetics, molecular biology, and environmental health and includes genomics, proteomics, and metabonomics, whereas functional genomics as described here is a specialized discipline that attempts to understand the functions of genes within cellular networks.
From page 108...
... 108 Toxicity Testing in the 21st Century High-throughput methods permit automation of such cell-based assays by the use of robots and libraries of cDNAs and siRNAs. The screens show which genes increase and which decrease activity of the toxicity pathway.
From page 109...
... 109 Tools and Technologies development and function of multicellular organisms. Computer models are helpful in understanding that complexity (Bhalla et al.
From page 110...
... 110 Toxicity Testing in the 21st Century evaluation of gene expression. Chapter 3 noted that careful design of those studies could substantially increase the value of information obtained.
From page 111...
... Those extrapolations will require some level of validation that might require data from kinetic studies in volunteers or from biomonitoring studies in human populations. In the committee's vision for toxicity testing, the development of PBPK models from SAR predictions of partition
From page 112...
... 112 Toxicity Testing in the 21st Century ing and metabolism would decrease animal use, and continued improvements in in vitro to in vivo extrapolations of kinetics will support the translation from test-tube studies of perturbations to predictions. Dose-Response Models of Toxicity Pathways Dose-response modeling of toxicity pathways involves the integration of mechanistic and dosimetric information about the toxicity of a chemical into descriptive mathematical terms to provide a quantitative model that allows dose and interspecies extrapolation (Conolly 2002)
From page 113...
... 113 Tools and Technologies In the next decades, the dose-response modeling tools for perturbations should progress relatively rapidly to guide lowdose extrapolations of initial interactions of toxic compounds with biologic systems. The quantitative lineage of early perturbations with apical responses is likely to develop more slowly.
From page 114...
... 1995. Modeling human interindividual vari ability in metabolism and risk: The example of 4-aminobiphenyl.
From page 115...
... 115 Tools and Technologies computational modeling of a combined rodent and human dataset.
From page 116...
... 116 Toxicity Testing in the 21st Century Huang, Q., A
From page 117...
... 117 Tools and Technologies Y Rombout, E
From page 118...
... 118 Toxicity Testing in the 21st Century melas, Tetrahymena pyriformis, and Vibrio fischeri.
From page 119...
... 119 Tools and Technologies Tong, W., W.J. Welsh, L


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