Ml. Cunningham et Hb. Matthews, CELL-PROLIFERATION AS A DETERMINING FACTOR FOR THE CARCINOGENICITY OFCHEMICALS - STUDIES WITH MUTAGENIC CARCINOGENS AND MUTAGENIC NONCARCINOGENS, Toxicology letters, 82-3, 1995, pp. 9-14
Recent work in our laboratory has examined mechanisms whereby chemical
s produce mutagenicity in short-term in vitro assays yet fail to produ
ce carcinogenesis in 2-year rodent bioassays. These studies have used
mutagenic structural analogs of carcinogenic and noncarcinogenic chemi
cals for comparison. Our previous studies have determined that differe
nces in the metabolism and disposition of these chemicals were not res
ponsible for their observed carcinogenic differences, but that carcino
genicity correlated with the ability of the respective isomer to induc
e cell proliferation in the target organ. Mutagenic noncarcinogens suc
h as 2,6-diaminotoluene (DAT), 1-nitropropane (NP), dimethoate, dioxat
hion, and dichlorvos failed to induce an increase in cell turnover in
the target organs. An increase in cell proliferation was observed foll
owing 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(R)) mice to detect in vivo muta
genesis induced by DAT isomers. Results of these studies demonstrate t
hat 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 indic
ate that cell proliferation may be requisite for expression of chemica
l-induced mutagenicity in vivo and thereby accommodate expression of c
arcinogenicity.