TABLE 3.

Factors that Limit the Carcinogenicity of DNA-Reactive Carcinogens and Potential Relevance for the MOA of Mouse Small Intestine Tumors Induced by Cr(VI)

Factors that limit carcinogenicity (Williams, 2008)	Limits Cr(VI) carcinogenicity?	Basis
Incomplete absorption/rapid excretion	Yes	Cr(VI) is reduced to Cr(III) in GI tract; Cr(III) is poorly absorbed and excreted in the feces
Binding to extracellular molecules	Yes	Cr(VI) reduction to Cr(III) is mediated by binding to organic molecules
Dilution upon systemic absorption	Not applicable	Point of contact effect, systemic absorption is not applicable
Low probability of reaching target stem cells	Yes	Cr(VI) may be partially or entirely reduced to Cr(III) before reaching the small intestine
	Unknown	Cr(VI) might not directly contact or be absorbed by proliferative crypt cells of the small intestine
Limited cellular uptake/efficient elimination at target site	Yes	Extracellular reduction of Cr(VI) to Cr(III) limits cellular uptake
	Unknown	Crypt cells might not express necessary transporters for absorption
Limited bioactivation or/efficient detoxification in target cells	Unknown	Intracellular reduction of Cr(VI) to Cr(III) might generate free radicals as well as Cr(III)-L species capable of interacting with DNA
Reaction with non-DNA nucleophiles	Unknown	(See previous)
Reaction with nonutilized regions of DNA	Yes	General phenomenon
Efficient DNA repair	Unknown	Cr(VI) might induce epigenetic changes that inhibit DNA repair
Low probability of producing transforming mutations in multiple critical genes	Unknown	Potential epigenetic factors
Infrequency of neoplastic development from preneoplastic lesion	Unknown	Persistent diffuse hyperplasia might increase the chance of neoplastic development