Threshold for Genotoxic Carcinogens: The Central Concern in Carcinogenic Risk Assessment

Genes and Environment

Hideki Wanibuchi²  Shoji Fukushima¹  Min Wei²  Anna Kakehashi² 

[1] Japan Bioassay Research Center, Japan Industrial Safety & Health Association;Department of Pathology, Osaka City University Graduate School of Medicine

关键词: carcinogenic threshold;    genotoxic hepatocarcinogens;    no additive or synergistic effects;    MeIQx;    IQ;    DEN;   

DOI  :  10.3123/jemsge.34.153

学科分类：分子生物学，细胞生物学和基因

来源: Japanese Environmental Mutagen Society / Nihon Kankyo Hen igen Gakkai

【 摘 要 】

References(11)Cited-By(1)To verify scientifically whether the non-threshold concept of genotoxic carcinogenicity is valid, we examined the hepatocarcinogenicities at low doses of three genotoxic carcinogens: 2-amino-3, 8 dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN) using a medium-term rat hepatocarcinogenicity bioassay. We also examined alterations of molecular markers that cells typically acquire as they move through the initiation and promotion stages of carcinogenesis. We found that low doses of MeIQx induced formation of DNA-MeIQx adducts, somewhat higher doses caused elevation of oxidative DNA damage, at further higher doses gene mutations occurred; and the very highest dose of MeIQx induced formation of glutathione S-transferase placental form (GST-P) positive foci in the liver, a well-known preneoplastic lesion marker in rat hepatocarcinogenesis. Similarly, low doses of IQ and DEN had no effect on formation of GST-P positive foci in the rat liver. Furthermore, we demonstrated that concurrent treatment with combinations of sub-carcinogenic doses of MeIQx and DEN were not hepatocarcinogenic and the combined effects were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic effects, and synergetic effects were observed only in rats co-administered high doses of those 2 carcinogens. These findings demonstrated the existence of no effect levels for these genotoxic hepatocarcinogens, and suggested that there is a threshold, at least a practical threshold, that should be considered when evaluating the risk of exposure to genotoxic carcinogens.

【 授权许可】

Unknown