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- Title
Threshold for Genotoxic Carcinogens: The Central Concern in Carcinogenic Risk Assessment.
- Authors
Fukushima, Shoji; Min Wei; Kakehashi, Anna; Wanibuchi, Hideki
- Abstract
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) andN-nitrosodiethylamine (DEN) using a mediumterm 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 eŠect 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 eŠects were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic eŠects, and synergetic eŠects were observed only in rats co-administered high doses of those 2 carcinogens. These findings demonstrated the existence of no eŠect 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.
- Subjects
CARCINOGENS; GENETIC toxicology; HEALTH risk assessment; LABORATORY rats; GENETIC mutation; BIOMARKERS; DNA damage
- Publication
Genes & Environment, 2012, Vol 34, Issue 4, p153
- ISSN
1880-7046
- Publication type
Article
- DOI
10.3123/jemsge.34.153