Existence of a Threshold for the Genotoxic Carcinogens: Evidence from Mechanism-based Carcinogenicity Studies

Abstract

The hepatocarcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a carcinogen contained in fried meat andˆsh, was examined in the mediumterm rat liver carcinogenicity bioassay. Induction of DNA-MeIQx adducts occurred with low doses of the chemical, followed by increasing doses by elevation of 8-hydroxy-2'deoxyguanosine (8-OHdG) formation in DNA and lacI gene mutations, which might have been related to the initiation of carcinogenesis by MeIQx. Further elevation of the MeI-Qx dose was shown to cause the formation of glutathione S-transferase placental form (GST-P) positive foci in the liver, a well-known preneoplastic marker in rat hepatocarcinogenesis. In studies with N-nitrosocompounds such as N-nitrosodiethylamine and N-nitrosodimethylamine, no induction of GST-P positive foci was observed after their administration at low doses. When the carcinogenicity of a well-known colon carcinogen 2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine (PhIP) was examined, PhIP-DNA adduct formation was observed after treatment with low doses, while only high doses of the chemical were found to induce aberrant crypt foci (ACF), which are a surrogate marker of preneoplastic lesions in the colon. In experiments with potassium bromate, carcinogenicity, mutagenicity, and 8-OHdG formation in the rat kidney were observed only after administration at high dose. From these results, the genotoxic carcinogens were concluded to have a threshold, at least practical, with respect to their carcinogenicity.

Carcinogenicity of multi-walled carbon nanotubes: challenging issue on hazard assessment

“…As discussed above, the genotoxicity data on MWNT-7 indicates that it is a genotoxic (mutagenic) agent that acts via a secondary mechanism (not directly DNA reactive). At present it is accepted that there should be a practical threshold for this kind of carcinogen 76 , 77) , and our carcinogenic threshold studies support this concept 71 , 72) . Based on the evidence of the existence of a practical threshold for MWNT-7 carcinogenicity, the NOAEL for carcinogenicity of MWNT-7 is 0.02 mg/m 3 in rats since exposure to this level did not result in the development of lung carcinomas in our study.…”

Cancer Risk at Ultra-low Dose: Lessons Learned from 40,000-animal Cancer Dose-response Studies

“…Thresholds: The concept of thresholds in genetic toxicology has received extensive recent review (5,(22)(23)(24)(25), and a number of reports have appeared presenting evidence for the existence of thresholds for genotoxic carcinogens. One example is a recent report by Fukiushima and colleagues (26), who reviewed the dose-response eŠects of 0.001-100 ppm dietary 2amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx) on several biomarkers of cancer risk in a medium term liver bioassay with 1145 male F344 rats. Although details were not given, the summary data reported sig-niˆcant increases for oxidative DNA damage at the three highest doses, for LacI reporter gene mutation at the two highest doses, and for MeIQx-DNA adducts as well as liver glutathione transferase P (GST-P) foci number and area at the highest dose only.…”

“…Tumor studies involving fewer animals, fewer dose replicates, or higher background rates will have lesser ability to discern doserelated responses relative to background, and thus an attendant higher risk level at which a practical threshold may be said to have been detected. Thus the rat MeIQx dose-response study (26) would provide more robust evidence for a practical threshold were more animals used at each dose, coupled with aˆner gradation of doses below 100 ppm. We committed 10,000 control (zero dose) animals in each of our two studies to provide an exhaustive estimation of background cancer rates in the organs of interest.…”

Is the Comet Assay a Sensitive Procedure for Detecting Genotoxicity?

“…This statement forms the basis of the “nonthreshold concept” in the risk assessment, which describes the absence of a threshold in genotoxic potential. The “nonthreshold concept” for genotoxic compounds means that these agents could have an influence on humans even at very low-levels [ 3 ]. Therefore, it is important to detect low level genotoxicity.…”