Lack of initiation activity in rat liver of low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline

Possible Involvement of Adaptation Mechanisms in the Achievement of an Ineffective Dose Range for the Carcinogenicity of Genotoxic Carcinogens

“…The presence of the identical ineŠective dose range was conˆrmed also for the development of hepatocellular neoplasia for MeIQx by the long-term carcinogenicity study in rats (10). Theseˆndings are supportive for the idea that a threshold may be present even for the carcinogenic eŠects of genotoxic carcinogens, and indicate a concept such that the earlier an event occurs during the carcinogenic processes, the smaller an ineŠective dose range is ( Fig.…”

“…There was a dogma insisting the absence of threshold levels for carcinogenic eŠects of carcinogens, because they were thought to be mostly mutagenic and interacting with DNA to cause irreversible genotoxicity with a strict dose dependency down to zero (1)(2)(3). Even after the general consensus about the existence of nongenotoxic carcinogens (indirectly aŠecting DNA and exerting carcinogenic eŠects through epigenetic mechanisms) and the presence of threshold levels for their carcinogenic eŠects (4)(5)(6), threshold levels are still believed absent for carcinogenic eŠects of genotoxic carcinogens (directly interacting with DNA and thereby exerting carcinogenic eŠects) because of their genotoxic nature itself, despite several challenging data (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

“…A 16-and 32-week multi-laboratory study was conducted using 1145 male 20-day-old Fischer 344 rats to assess detailed dose-dependency of hepatocarcinogenic eŠects of a heterocyclic amine, 2-amino-3,8-dimethylimidazo [4,5-f ]quinoxaline (MeIQx), featuring the lowest dietary dose of 0.001 ppm that is relevant to the human exposure level (10,11,14). As a result, MeIQx-DNA adduct was formed for all assessed doses, of which level increased according to the dose increment in the liver.…”

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

“…Therefore, the concept of a dose threshold for chemical carcinogenicity has been discussed and challenged. Fukushima et al 9 mentioned that MeIQx must have both initiating and promoting activities with reference to the 2-stage mechanism of the hepatocarcinogenesis in rats, and they concluded that a no-observed effect level may exist for the hepatocarcinogenic potential. According to Lutz, 11 a practical threshold is used to describe a dose-related increment as negligible in view of extent and variability of the background process, which is based on the idea that carcinogenic processes can be accelerated or slowed down in a number of ways in vivo because of effects on DNA damage, DNA repair, replication, chromosomal and genomic integrity.…”

“…7 Thereby, in our laboratory, the nonthreshold theory for hepatocarcinogenesis of one HCA, 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx), has been challenged, since in vivo dose-response curves do not show linearity at low-dose levels. 8,9 Moreover, thresholds for chemical carcinogenesis were concluded in a recent article. 10 In practice, the many factors active in vivo, from intake of carcinogens through to lesion development, mean that the processes are highly complicated, so that if the DNA-damaging potency of a carcinogen is low, the linear part of the low dose-cancer incidence curve might be hidden within the background variability, and issues of true threshold and practical threshold have therefore been discussed.…”