Application of Modern Toxicology Approaches for Predicting Acute Toxicity for Chemical Defense (2015) / Chapter Skim
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2 Conceptual Framework and Prioritization Strategy
2 Conceptual Framework and Prioritization Strategy
Pages 13-28
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From page 13... ...
: A conceptual framework that links chemical structure, physicochemical properties, biochemical properties, and biological activity to acute toxicity. A suite of databases, assays, models, and tools that are based on modern in vitro, nonmammalian in vivo, and in silico approaches applicable to predicting acute toxicity.
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The vast majority of available toxicity information has come from traditional toxicity studies in which adverse biological responses were measured in laboratory animals that were exposed to high doses of a test agent. The acute-toxicity data are often used to provide estimates of the amount of an agent that would be required to kill 50% of a population of test animals, such as a lethal dose 50% (LD50)
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A FRAMEWORK AND STRATEGY FOR PREDICTING ACUTE TOXICITY OF POTENTIAL CHEMICAL-WARFARE AGENTS Conceptual Framework A predictive-toxicology program to assess acute toxicity ideally will build on knowledge about the cellular targets and mechanisms of action that are related to acute human toxicity. Acute toxicity depends on fewer biological and chemical pathways than those envisioned by NRC (2007)
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2010) assays for Altered serotonin reuptake Fluoxetine acetylcholinesterase inhibitors Altered dopamine reuptake Amphetamine Altered ion flow Altered electrical conduction of heart Sodium–potassium Digoxin Cardiovascular Assessment of altered cardiomyocyte or cardiomyocyte contractility ATPase blockers contraction (Himmel 2013; Pointon et al.
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(TRPA1) activation Chemical reactivity Acylation of proteins and lipids Phosgene Respiratory Human epithelial lung cells as a system to (pulmonary edema)
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, sulfur Multiple Medium-throughput methods for mustard quantification of sulfur mustard adducts to proteins (Andacht et al. 2014; Pantazides et al.
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Specifically, it is hypothesized that chemical structure, physicochemical properties, biochemical properties, or biological activity in isolated cells and tissues or in nonmammalian organisms can predict acute mammalian toxicity. The predictions can arise through observations of empirical or statistical correlations or through knowledge of the relevant mechanistic pathways, either of which could potentially be coupled with toxicokinetic information.
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Prioritization Strategy for Evaluating Acute Toxicity Effective implementation of predictive models and tools depends on first identifying the ultimate (and acceptable) use of the predictive outputs.
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However, as a general approach, the committee found that the policy tradeoff could be managed through a tiered prioritization approach as illustrated in Figure 2-2. Specifically, the committee's proposed prioritization strategy proceeds through a number of tiers that apply successively more predictive and resource-intensive approaches than the previous ones.
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The committee broadly grouped the available approaches to predicting acute toxicity into four tiers, beginning with an initial chemical characterization (Tier 0) , proceeding to nontesting approaches (Tier 1)
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Tier 0 would be an initial chemical characterization of toxicity and physicochemical properties based on existing data. In addition to characterizing acute toxicity, traditional toxicity data can be used to build and test predictive-toxicology models in Tiers 1 and 2, and physicochemical data might be important for understanding potential exposure routes, bioavailability, target-tissue dis tribution, and potential physical hazards or chemical reactivity associated with an agent.
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And, it is up to DOD to determine the extent of coverage of end points that is adequate for it to make sufficiently reliable decisions at each tier. FINDINGS AND RECOMMENDATIONS Finding: There are multiple mechanisms by which chemicals can elicit acute, debilitating toxicity, and these mechanisms provide support for a predictive-toxicology conceptual framework that predicts system, tissue, or organism toxicity on the basis of chemical structure, physicochemical properties, biochemical properties, or biological activity in isolated cells, tissues, and lower organisms.
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2014. An enhanced throughput method for quantification of sulfur mustard adducts to human se rum albumin via isotope dilution tandem mass spectrometry.
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2015. Simplified method for quantifying sulfur mustard adducts to blood proteins by Ultra high Pressure Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry.
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2013. Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity.
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2013. High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury.
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