Use of Dose-Response Data for in vivo Mutagenicity to Inform Cancer Risk Assessment

If the chemical causes cancer via a mutagenic mode-of-action three basic predictions exist:

bullet The frequency of induced mutations per target tissue will be higher than the frequency of tumors per target tissue.

bullet Mutations will be observed prior to the observation of tumors (temporal relationship).

bullet If a chemical is a mutagenic carcinogen, mutations should be induced at doses lower than those required to form tumors (dose-response).

Preliminary collaborative work between NCTR (led by Martha Moore, Bob Heflich and Ralph Kodell) and Bruce Allen and Annette Shipp of Environ has found promising results for distinguishing the role of mutagenesis in carcinogenicity by chemicals that are mutagens (as defined by a series of genotoxicity/mutagenicity tests) and carcinogens, but which may or may not have mutation as their primary mode of carcinogenic action. Better consideration of the impact of mutagenicity in the mode of action of these types of carcinogens would put cancer risk assessment, linear or not, on a firmer foundation.

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