What's new in mutagenicity and carcinogenicity--status of short-term assay systems as tools in genetic toxicology and carcinogenesis.
The status of short term assay systems as tools in genetic toxicology has shifted from the goal to predict carcinogenic activity of chemicals toward their employment for understanding and elucidating the mechanisms of biological activity. This altered mode of application arises from research development in two main areas. One resulted in the observation that the calculated predictive values of individual assay systems (alone or in combination with supplementary tests) to detect carcinogens as genotoxic and non-carcinogens as non-genotoxic are lower than originally expected. The other is the increasing recognition that by employing relevant in vitro procedures, various aspects of a compound's activity can be studied which may otherwise not be clarified with available in vivo methods. This report focuses on the reasons why mutagenesis assays, or short term genotoxicity assays, in general, are not unambiguously employed for determining the carcinogenic potential of unknown compounds. One reason is that a safe prediction is not possible, since non-genotoxic carcinogens will not induce alterations of the DNA. Another reason is that even genotoxic carcinogens may not accurately respond as positive in a given test system due to the limitations of the specific assay. These are mainly seen in the incomplete metabolic conversion of the test compound, irrelevancy the measured effect may actually have for carcinogenesis, and the lack of regarding pharmacokinetic influences by a host animal, when testing in vitro. A rationale testing strategy compiled of assay systems which individually are included to overcome the restrictions is described.(ABSTRACT TRUNCATED AT 250 WORDS)
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Institute for Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, FRG.
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D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism; D004252:DNA Mutational Analysis; D006801:Humans; D009152:Mutagenicity Tests; D011237:Predictive Value of Tests; D013997:Time Factors
D002273:Carcinogens