Evidence of a Threshold-Effect for 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline Liver Carcinogenicity in F344/DuCrj Rats

Abstract

To estimate potential human risk of exposure to a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a 2-year carcinogenicity test was conducted using male F344 rats administered MeIQx-containing diet at doses of 0 (control), 0.001, 1, and 100 ppm. The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 μg/man/day). Significant decreases of survival rate and body weight gain were observed in rats treated with 100 ppm MeIQx. Histopathological examination revealed significant induction of hepatocellular carcinomas, adenomas, and development of glutathione S-transferase placental form-positive foci with MeIQx at 100 ppm. Moreover, the incidences of Zymbal's glands carcinoma, mammary fibroadenoma, and subcutaneous fibroma were found significantly increased in a 100 ppm MeIQx group. However, no significant induction of altered preneoplastic hepatocellular foci was observed in 0.001 and 1 ppm groups as compared to the controls. 8-Hydroxy-2'-deoxyguanosine levels in the rat liver DNA of the 100 ppm-treated group were not elevated, but MeIQx-DNA adduct formation increased as compared with the 1 ppm case, albeit without significance. No significant induction of any other neoplastic lesions related to the carcinogen administration was found in MeIQx-administered groups except for 100 ppm. These results imply that 1 ppm may be a no-effect level for MeIQx carcinogenesis.

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

“…Thus, from the investigation of the markers, which are indicators of hepatocarcinogenesis, the no-observed eŠect level was detected for each of them, and according to the analysis on the basis of carcinogenicity mechanisms, it has been concluded that MeIQx has a threshold, at least a practical threshold, for its hepatocarcinogenicity in the rat. Indeed, our 2-year carcinogenicity test with MeIQx in rats showed no hepatocarcinogenicity at low doses (6).…”

Molecular events in hepatic preneoplasia: A review

“…Markers used for identifying preneoplastic foci include glutathione S transferase placenta (GSTP) GSTmu, GSTpi (Inoue et al, 2008; Nishimura et al, 2008; Scolastici et al, 2008; Murae et al, 2008; Satoh et al, 2008; Fan et al, 2008; Perra et al, 2009; Sukata et al, 2004; Nagao et al, 1999; Roomi et all, 2006; Oliva et al, 2008; Oliva et al, 2009), diubiquitin (FAT10) (Nan et al, 2006; Evert et al, 2005) fatty acid synthase (FAS) (Tazawa et al, 1983; Nagao et al, 1998) gamma glutamyltransferase (GGT) (Perra et al, 2009; Oliva et al, 2009; Nan et al, 2006; Lee et al, 2003) α2 macroglobulin (α2M)) (Nagao et al, 1999; Tazawa et al, 1983) and alpha fetoprotein (AFP) (Tazawa et al, 1983). …”

Experimental Design and Statistical Analysis of Studies to Demonstrate a Threshold in Genetic Toxicology: A Mini-review

“…Historical data on the inter-experimental unit variability can be used to provide estimates of the size of a standard deviation unit. The level of eŠect detectable in an experiment is illustrated using GST-P positive foci data from Table 3 in Murai et al (52). The negative control mean is 22.9 foci with approximate inter-individual within group standard deviations of about 5 foci.…”