Carcinogenicity testing tiers

Based upon the above rationale, a tier approach in carcinogenicity testing and assessment of pharmaceuticals can be followed, possibly with refinement,... 

The most successful application of structure-based predictive modeling in the future may be to specific endpoints. As described in Chapter 8 the prediction of something as broad as carcinogenicity is very difficult. If one isolates individual effects and endpoints within this category, then more success will ensue. Such an approach is likely to require the development of tiered strategies for toxicity prediction. It will also allow for the integration of test data from other assays, and where possible, human knowledge. 

The major deviations from this orderly structure are the test requirements concerning mutagenicity and carcinogenicity, that form a special tiered approach, and the provisions for waiving certain test requirements. 

As discussed in FDA s Preparation of Food Contact Notifications for Food Contact Substances Toxicology Recommendations (FDA, 2002), FDA has set forth minimum testing recommendations for tiered levels of expected consumer exposure. These recommendations are based on the general principle that the potential risk is likely to increase as exposure increases. In addition, submitters are encouraged to discuss the structural similarity of their food contact material or its constituents to known mutagens or carcinogens. This analysis is termed structure-activity relationship (SAR) analysis and is recommended for all exposures (discussed further below). Table 7.1 summarizes... 

A weight-of-evidence or tier approach to the level of suspicion of carcinogenic risk will be the main objective, and will include SAR and findings from sub-chronic to chronic toxicity testing (genotoxicity, reproductive toxicity, and organ toxicity). In addition, communication between industry and regulatory authorities will be formulated early in order to allow the most optimal scientific approach. 

A Battery vs. a Tier of Short-Term Tests for Identifying Potentially Carcinogenic Chemicals... 

Tier 3 attempts to quantitate the real mutational risk to man and to evaluate the risk in relation to actual benefits. It is crucial to this tier that the test systems for quantitation be as organizationally human as possible. Hence, carcinogenicity and mutagenicity will be evaluated in whole mammals as such or in a host-mediated assay that utilizes mammalian indicators. 

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