Research in this laboratory is directed to investigations of metabolic and dispositional factors which account for """"""""false positive"""""""" mutagenic noncarcinogens in the whole animal to explain the observed nonconcordance between results of short-term genotoxicity assays and chronic bioassays. Studies with the mutagenic carcinogen-noncarcinogen pair 2, 4- and 2 6-diaminotoluene (DAT) demonstrated that the carcinogenic isomer produced a dose-related increase in cell proliferation in the liver, the target organ for carcinogenesis, whereas the noncarcinogen produced no increase in cell proliferation even at higher doses. We have employed the incorporation of bromodeoxyuridine into newly synthesized DNA and localization by immunohistochemistry to quantitate cell proliferation. Recent results with the mutagenic noncarcinogen-carcinogen pair 1- and 2-nitropropane (NP) demonstrated the hepatocarcinogenic isomer 2-NP produced a dose-related increase in cell proliferation in the liver yet the noncarcinogenic isomer 1-NP did not. Results of these two studies suggest a positive correlation between cell proliferation and carcinogenicity for these chemicals, irrespective of their mutagenicity. We have also characterized biochemical changes resulting from such chemically induced cell proliferation. For instance, following treatment with Mirex, the liver undergoes rapid cell proliferation accompanied by increased oxygen consumption, depleted glycogen, stores and increased rates of lactate and pyruvate production. The increased rate of cell proliferation is believed to be dependent on corticosterone since chemical treatment in adrenalectomized rats reduced the extent of liver growth. Future research will expand these findings with other chemical pairs, especially mutagenic carcinogen-noncarcinogen pairs whenever possible to further evaluate the role of cell proliferation in experimental carcinogenesis, and further characterize the biochemical and physiological regulation of liver growth in response to chemical treatment.

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