Testing for carcinogens: shift from animals to automation gathers steam--slowly.
- SourceAvailable from: Alessandro Giuliani[Show abstract] [Hide abstract]
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.Expert Opinion on Drug Metabolism & Toxicology 07/2010; 6(7):809-19. DOI:10.1517/17425255.2010.486400 · 2.93 Impact Factor
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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.Journal of Environmental Science and Health Part C Environmental Carcinogenesis & Ecotoxicology Reviews 10/2010; 28(4):272-86. DOI:10.1080/10590501.2010.525781 · 2.50 Impact Factor
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ABSTRACT: Long-term rodent bioassays have played a central role in protecting human health from carcinogens; for ethical and practical reasons their use is decreasing whereas genotoxicity testing has taken a pivotal role. However, this strategy-as presently implemented-is not sensitive enough to detect all genotoxic carcinogens, and cannot detect nongenotoxic carcinogens. Among the alternative approaches under study there is the ToxCast/Tox21 project. Following a previous study from our laboratory, here we present a new, more extensive analysis of ToxCast Phase I results, indicating that at the present state-of-art this approach is not able to predict the carcinogenicity of chemicals. Possible reasons for this mediocre performance are discussed, and opinions on ways to tune up the project in the next phases are presented.Journal of Environmental Science and Health Part C Environmental Carcinogenesis & Ecotoxicology Reviews 01/2013; 31(3):201-12. DOI:10.1080/10590501.2013.824188 · 2.50 Impact Factor