Testing for Carcinogens: Shift From Animals to Automation Gathers Steam--Slowly

Journal of the National Cancer Institute (Impact Factor: 12.58). 07/2009; 101(13):910-2. DOI: 10.1093/jnci/djp191
Source: PubMed

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    • "In response to increased concerns about neurotoxicity induced in humans by exposure to chemicals during development , the scientific community is developing alternatives that will reduce the use of traditional laboratory animals while addressing the demand for increased and more relevant testing . In addition, more than 30,000 chemicals without adequate toxicological information are estimated to be in use in the United States and Europe (Schmidt, 2009), and the task of testing thousands of chemicals systematically with classical animal tests exceeds our present capabilities. In 2008, in response to the US National Academy Q5 of Sciences' report on " Toxicity Testing in the 21st Century " (NRC, 2007), a collaboration was established between the National Institute of Environmental Health "
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    ABSTRACT: Induced pluripotent stem cells (iPSC) and their differentiated derivatives offer a unique source of human primary cells for toxicity screens. Here, we report on the comparative cytotoxicity of 80 compounds (neurotoxicants, developmental neurotoxicants, environmental compounds) in iPSC as well as isogenic iPSC-derived neural stem cells (NSC), neurons, and astrocytes. All compounds were tested over a 24-hour period at 10 and 100μM, in duplicate, with cytotoxicity measured using the MTT assay. Of the 80 compounds tested, 50 induced significant cytotoxicity in at least one cell type; per cell type, 32, 38, 46, and 41 induced significant cytotoxicity in iPSC, NSC, neurons, and astrocytes, respectively. Four compounds (valinomycin, 3,3',5,5'-tetrabromobisphenol, deltamethrin, triphenyl phosphate) were cytotoxic in all four cell types. Retesting these compounds at 1, 10, and 100μM using the same exposure protocol yielded consistent results as compared with the primary screen. Using rotenone, we extended the testing to seven additional iPSC lines of both genders; no substantial difference in the extent of cytotoxicity was detected among the cell lines. Finally, the cytotoxicity assay was simplified by measuring luciferase activity using lineage-specific luciferase reporter iPSC lines which were generated from the parental iPSC line. Copyright © 2015. Published by Elsevier B.V.
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    ABSTRACT: Carcinogenicity and mutagenicity are toxicological end points posing considerable concern for human health. Due to the cost in animal lives, time and money, alternative approaches to the rodent bioassay were designed based on: i) identification of mutations and ii) structure-activity relationships. Evidence on i) and ii) is summarized, covering 4 decades (1971 - 2010). A comprehensive, state-of-the-art perspective on alternatives to the carcinogenicity bioassay. Research to develop mutagenicity-based tests to predict carcinogenicity has generated useful results only for a limited area of the chemical space, that is, for the DNA-reactive chemicals (able to induce cancer, together with a wide spectrum of mutations). The most predictive mutagenicity-based assay is the Ames test. For non-DNA-reactive chemicals, that are Ames-negative and mutagenic in other in vitro assays (e.g., clastogenicity), no correlation with carcinogenicity is apparent. The knowledge on DNA reactivity permits the identification of genotoxic carcinogens with the same efficiency of the Ames test. Thus, a chemical mutagenic in Salmonella and/or with structural alerts should be seriously considered as a potential carcinogen. No reliable mutagenicity-based alternative tools are available to assess the risk of non-DNA-reactive chemicals.
    Full-text · Article · Jul 2010 · Expert Opinion on Drug Metabolism & Toxicology
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    ABSTRACT: The research on alternative toxicological methods provides, among other things, a privileged viewpoint on one of the central issues of modern biomedical research--the relationship between (a) biological phenomena observed at the level of tissues and organisms and (b) their cellular and molecular bases as studied in isolated systems in vitro. The newly released ToxCast Phase 1 results, subject to initial analysis, converge with evidence from other fields (e.g., research on drug design with intensive use of omics technologies, traditional research on alternative tests) in indicating a low degree of the in vitro/in vivo correlation overall. In addition, this and other approaches point to the need for combining biological and chemical information in exploring the in vitro to in vivo connection.
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