Cell proliferation as a determining factor for the carcinogenicity of chemicals: studies with mutagenic carcinogens and mutagenic noncarcinogens.
Recent work in our laboratory has examined mechanisms whereby chemicals produce mutagenicity in short-term in vitro assays yet fail to produce carcinogenesis in 2-year rodent bioassays. These studies have used mutagenic structural analogs of carcinogenic and noncarcinogenic chemicals for comparison. Our previous studies have determined that differences in the metabolism and disposition of these chemicals were not responsible for their observed carcinogenic differences, but that carcinogenicity correlated with the ability of the respective isomer to induce cell proliferation in the target organ. Mutagenic noncarcinogens such as 2,6-diaminotoluene (DAT), 1-nitropropane (NP), dimethoate, dioxathion, and dichlorvos failed to induce an increase in cell turnover in the target organs. An increase in cell proliferation was observed following exposure to the mutagenic carcinogen analogs 2,4-DAT (liver), 2-NP (liver), and tris(2,3-dibromopropyl)phosphate (kidney). Our recent studies have used transgenic (Big Blue) mice to detect in vivo mutagenesis induced by DAT isomers. Results of these studies demonstrate that administration of the carcinogenic isomer, 2,4-DAT, resulted in an increase in in vivo mutation frequency, whereas administration of the noncarcinogenic isomer, 2,6-DAT, failed to do so. These results indicate that cell proliferation may be requisite for expression of chemical-induced mutagenicity in vivo and thereby accommodate expression of carcinogenicity.
Cunningham
M L
ML
Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Matthews
H B
HB
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D010655:Phenylenediamines / Q000633:toxicity
D002273:Carcinogens; D009153:Mutagens; D010655:Phenylenediamines; C025235:2,6-diaminotoluene; C010914:2,4-diaminotoluene