No-Observed Effect Levels for Carcinogenicity and for in vivo Mutagenicity of a Genotoxic Carcinogen

Abstract

To elucidate the relationship between in vivo carcinogenic and mutagenic potentials of genotoxic carcinogens, low doses were tested in the livers of Big Blue transgenic rats with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Male Big Blue rats were fed a diet containing 0.001, 0.01, 0.1, 1, 10, or 100 ppm of MeIQx for 16 weeks, and the frequencies of lacI mutants and glutathione S-transferase placental form (GST-P) positive foci in the liver were determined. The mutation frequencies significantly increased at doses of 10 and 100 ppm, and GST-P positive foci significantly increased at a dose of 100 ppm. However, no statistical increases in both frequencies were observed at lower doses. MeIQx most frequently induced G frameshifts, followed by G to T transversions. Thus, no observed effect level (NOEL) was demonstrated for both carcinogenicity in terms of preneoplastic lesion induction and in vivo mutagenicity of MeIQx, and the NOEL for in vivo mutagenicity was lower than that for carcinogenicity.

Do 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline data support the conclusion of threshold carcinogenic effects?

“…Fukushima et al (2003) further suggested that low MeIQx exposure doses lack initiation activity in rat liver. A similar suggestion was also made by Hoshi et al (2004) based on liver GGT+ foci data; they hypothesized that MeIQx lacks direct mutagenicity and thus would exhibit a threshold for carcinogenicity. Recently, Fusushima and associates (Wei et al 2006) also use liver GGT+ foci data to show that a no effect level exists not only for Fisher 344 rats but also for BN rats.…”

“…Recently, Fusushima and associates (Wei et al 2006) also use liver GGT+ foci data to show that a no effect level exists not only for Fisher 344 rats but also for BN rats. The conclusion of a carcinogenic threshold by both Fukushima et al (2002Fukushima et al ( , 2003, Wei et al (2006), and Hoshi et al (2004) was based on the lack of statistical significance between dosed and control groups at all but the two highest exposure levels. While the GGT+ focus is a useful marker for tumor initiation, it is commonly recognized that the absence of statistical significance between control and low dosed groups alone cannot be used to establish a threshold effect for carcinogenicity or initiation activity.…”

IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk

“…Rats exposed to this carcinogen were examined to determine the formation of 1) MeIQx-DNA adducts [105], 2) mutations at the H-ras locus [106] and in LacI transgenes [107], 3) pre-neoplastic lesions (PNL) in the form of GST-positive foci [105], and 4) hepatocellular adenomas and carcinomas [108]. These endpoints were evaluated at 4, 16, 16-32 and 56 weeks of repeat dosing, respectively.…”

The initiation activity of norfloxacin does not result in the induction of hepatocellular tumors in rats

“…However, the prevailing paradigm is that genotoxic carcinogens have no threshold for exerting their potential for tumor induction. Meanwhile, recently, there are increased numbers of reports supporting that low doses of some genotoxic carcinogens showed a practical threshold as in so-called nongenotoxic carcinogens (Tsuda et al, 2003;Hoshi et al, 2004). From the viewpoint of this new paradigm, there is a very low possibility that hepatocellular tumors are induced in the NFLXtreated patients and the consumers ingesting food that is contaminated with NFLX.…”