Using 21st Century Science to Improve Risk-Related Evaluations (2017) / Chapter Skim
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3 Advances in Toxicology
3 Advances in Toxicology
Pages 51-78
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From page 51... ...
questions to which the tools could be applied are the fol lowing: • Large banks of immortalized cells that are derived from lymphocytes and collected from different • Planning and scoping: Which chemicals should populations worldwide are available for toxicological re- undergo comprehensive toxicological evaluation first search. (that is, how should priorities be set among chemicals for • Genetically diverse mouse strains have been cre- testing)
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ultimate goal is prediction of the response of the organism Advances in pharmacokinetic analyses and models were or population to exposure, and different tools can be used discussed in Chapter 2 and are not elaborated on further Interactions Outcome: External External Internal Target Tissue and Organism and with biological Cell response exposure Exposure Exposure Exposure organ response population molecules response Pharmacokinetic models Computational Models Cheminformatics Docking models Systems biology models Methods in Toxicology Virtual tissue models Read-across and structure-activity-relationship (SAR) models SAR Models Population models Pharmacokinetic studies Assays and other studies Cell-free assays Cell-culture assays Organotypic studies Studies in integrated systems and novel species Studies in genetically diverse integrated systems and molecular epidemiology FIGURE 3-1 Computational models and biological assays are shown with the exposure-to-outcome continuum to illustrate where the models and assays might be used to provide information at various points in the pathway.
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From page 53... ...
interactions associated with a novel chemical structure with a reported average accuracy of over 92% with some PREDICTING AND PROBING proteins and high selectivity; that is, only small numbers INTERACTIONS OF CHEMICALS of active predictions were later shown to be negative in WITH CELLULAR COMPONENTS vitro. Although most of the activities were predicted cor rectly, it was at the expense of a high false-positive rate Chemical interactions with specific receptors, en- (that is, large numbers of inactive chemicals were predictzymes, or other discrete proteins and nucleic acids and ed to be active)
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nology has evolved to the point where many cell lines 2013)
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Furthermore, although some assay systems Cell cultures can be grown in a variety of architec- might capture metabolism in the liver, extrahepatic metures, including monolayer and 3-D cultures of cell lines, tabolism might be the driver of some chemical toxicity, and can be used as indicators of possible tissue, organ, so the spectrum of relevant in vivo metabolic activation is and sometimes organism-level signs of possible toxicity, an important consideration in understanding the validity particularly in integrated systems that consider effects and of in vitro studies and interpreting the results from both signaling among cell types (Zhang et al.
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. However, more than the conventional monolayer cultures A major advance in primary cell culture over the last of primary cells, immortalized cell lines can lose native in decade is the development of 3-D cultures of cell lines.4 vivo properties and functionality.
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of three primary types: embryonic, adult, and induced A few simple structural units that have specific funcpluripotent stem cells. Embryonic stem cells are har- tions and appear repeatedly in different species are revested from embryos that are less than 5 days old and ferred to as network motifs (Milo et al.
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. Several organ-on-a-chip models have models of tissue and computational models for simulating been engineered, including ones for liver, heart, lung, inresponse at the tissue level (see Figure 3-4)
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. Researchers face challenges in developing such ex- As discussed earlier, computational systems biology perimental platforms, for example, with the synthetic might be used to describe pathway perturbations that are materials used in the manufacture of the cell-culture caused by chemical exposures and the resulting cell resubstrates.
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emphasized a future ticellular responses. The cellular responses alter tissue in which routine toxicity testing would rely on in vitro asfunction; the quantitative modeling then focuses on the says with human cells or assays that probe molecular reinterface between the cellular-level computation models sponses of human toxicity pathways and pathway compoand virtual-tissue models.
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Targeted testing will be critically important dent species and strains. Although there are advantages in evaluating and validating the robustness and reliability in using a well-characterized strain of mice or rats to test of new computational models, in vitro assays, and test- chemical toxicity, there are many shortcomings, including batteries (Andersen and Krewski 2009; Krewski et al.
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To tools uniquely suited for these emerging animal models address the challenge in TCE-toxicity testing, a battery of are available and readily adaptable to toxicological testmouse lines was used to assess interindividual variability ing (Zhang et al. 2012b; Morgan and Welsh 2015)
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. The adult zebrafish is increasingly used to measure neurobiological end points affected by chemical exposures.
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computational models are being accepted as surrogates Because the developing embryo constitutes a comprehen- for actual testing and have recently been incorporated into sive integrated system, all potential molecular initiating international guidelines for assessing mutagenic impurievents are operational during testing. Thus, zebrafish are ties in pharmaceuticals to limit potential carcinogenic risk uniquely sensitive to chemical contaminants present in (ICH 2014)
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(2013) extended the concept of similarshow comparable effects of all the developmentally toxic ity in read-across from chemical structure to bioactivity, phthalates (Liu et al.
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Figure 3-8 illustrates several scenarios for read-across and how it can Challenge: Obtaining the vision described in the be used to infer hazard and dose–response relationships. Tox21 report in which traditional whole-animal testing is replaced with a broad toxicity-testing strategy that uses INCORPORATING DATA STREAMS primarily in vitro assays, computational methods, and tar geted animal testing for assessing the biological activity Various chemicals will have multiple data streams of chemicals is a complex and labor-intensive task that along the exposure-to-outcome continuum that can be requires focus, commitment, and resources (NRC 2007)
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Anchor chemicals show similar and Dose-Response: Adjust for pk PAHs related but not identical hazards and bioactivity after testing how determinants of human variability (for example, un- needs of the pharmaceutical industry and were not dederlying nutritional, genetic, or disease state or life stage) signed to cover the full array of biological response, given and exposure duration might affect biological responses the extensive testing in whole animals and humans that or toxicity.
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Genetic vari Understanding and Addressing ability, phenotypic characteristics, and purity should be Limitations of Cell Systems reported in published literature or on publicly accessible Web sites or interfaces. Challenge: Substantial progress has been made in de- Recommendation: Assay development should be coveloping and adapting a wide array of assays for screening ordinated with development of computational models of environmental chemicals, but cell cultures have several cellular responses involved in pathway perturbations to important limitations.
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tion of integration-free human induced pluripotent stem Environ. Health Perspect.
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Broman, K.J. Buck, out: Antitarget QSAR models for drug development.
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generated from pluripotent stem cell-derived neural stem Judson, D Knight, D
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Bogue, K eration of hepatocytes from pluripotent stem cells for drug Paigen, C
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:498-503. duced pluripotent stem cell-derived neuronal cells from a Huh, D., G.A.
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Human induced pluripotent stem cell-derived car- zebrafish leading to degenerative myopathy and impaired diomyocytes: Insights into molecular, cellular, and func- swimming behavior.
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2007. Toxicity Testing toxicity.
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Giannone, duced pluripotent stem cells and their use in drug discov P.A. Harper, J
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:1975-1984. nisms in induced pluripotent stem cell-derived hepato- Threadgill, D.W., and G.A.
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icity with human induced pluripotent stem cell-derived J Toxicol.
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