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Min Wei Anna Kakehashi Shotaro Yamano Seiko Tamano Tomoyuki Shirai Hideki Wanibuchi Shoji Fukushima 《Journal of toxicologic pathology》2012,25(3):209-214
The purposes of the present study were to evaluate the hepatocarcinogenicity of
concurrent treatment of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
(MeIQx) and diethylnitrosamine (DEN) in rats and to determine whether no effect levels of
combinations of these two different structural categories of genotoxic hepatocarcinogens
exist. Two 16-week rat hepatocarcinogenesis assays were performed using a total of 790
male F344 rats. In experiment 1, we evaluated the effects of concurrent treatment of a
subcarcinogenic dose of DEN on rat hepatocarcinogenesis induced by various doses of MeIQx.
In experiment 2, we determined hepatocarcinogenicities of combinations of MeIQx and DEN at
subcarcinogenic doses, low carcinogenic doses and high carcinogenic doses. Quantitative
analyses of glutathione S-transferase placental form (GST-P)-positive
foci, a preneoplastic lesion of the liver in rats, revealed that concurrent treatment with
subcarcinogenic doses of DEN did not enhance MeIQx-induced rat hepatocarcinogenicity. We
also found that concurrent treatment with combinations of subcarcinogenic doses of DEN and
MeIQx was not hepatocarcinogenic, indicating that the combined effects of subcarcinogenic
doses of DEN and MeIQx were neither additive nor synergistic. Moreover, concurrent
treatment with low carcinogenic doses of these 2 carcinogens did not show additive or
synergistic effects. Synergetic effects were observed only in rats coadministered high
carcinogenic doses of the 2 carcinogens. These results demonstrate the existence of no
effect levels of combinations of these 2 genotoxic hepatocarcinogens, and provide new
evidence supporting our idea that there is a threshold, at least a practical threshold,
that should be considered when evaluating the risk of genotoxic carcinogens. 相似文献
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