Genetic toxicity testing approaches

For a constituent of an additive with equivocal (mixed positive and negative) battery of genetic toxicity tests and a EDI of < 150 pg/p/d, SAR analysis for SAs and predictive software such as MDL QSAR (Contrera et al, 2005) and MultiCASE s MC4PC (Rosenkranz and Klopman, 1988 Matthews and Contrera, 1998) may be used as part of the weight of evidence approach in assessing the safety of the compound. If a constituent were of potential concern, a quantitative SAR analysis might be feasible to characterize the expected risk. 

This theoretical example of a QSAR assessment is presented to exhibit FDA s current approach to using S AR as a tool in the safety evaluation of substances proposed for use as food contact materials. If anthrafurin (1,6-dihydroxy anthraquinone CASRN 117-12-4 Fig. 7.3) were expected to be an impurity in a food contact material, an immediate initial concern would be raised due to reports in the literature of positive results in the bacterial reverse mutation assay and other in vitro genetic toxicity tests. A literature search did not identify relevant carcinogenicity data for anthrafurin. 

In the hierarchy of toxicity testing, the use of structure-activity relationships is becoming an increasingly important predictive tool. The reliability of this tool is, of course, dependent on the accuracy of the data bases which it incorporates. Efforts are under way to make these bases more reliable. Further steps in safety evaluation may follow a "decision tree" approach any scheme adopted should involve a variety of screening procedures, including tests for genetic toxicity, as well as early studies of metabolism and pharmacokinetics. 

The development of the assay system or new testing approach will be based on the use of model compounds with known mechanisms of action. If the assay system appears to be a reliable and sensitive indicator of genetic toxicity, it will be subjected to validation under controlled conditions. 

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