Existence of no-observed effect levels for 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline on hepatic preneoplastic lesion development in BN rats
Introduction
Exposure to environmental carcinogens is one of significant causes of human cancers. Some of environmental carcinogens cannot be completely eliminated, therefore, it is very important to assess and manage the potential risks associated with human exposure to these agents. Dose–response assessment defines the relationship between the dose of an agent and the probability of induction of a carcinogenic effect, and is one of the most important components of carcinogen risk assessment. The dose–response relationship for genotoxic carcinogens is generally assumed to be linear without a threshold dose below which carcinogenic effects are absent, meaning that genotoxic carcinogens may pose some risk at any level of exposure [1], [2], [3], although there is no definitive experimental evidence to support this suggestion.
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a heterocyclic amine detected in the cooked meat and fish, is a potent genotoxic carcinogen [4], [5]. MeIQx induced hepatocellular carcinoma in male F344 rats at high doses [6], [7]. However, our recent low-dose studies showed the existence of no-observed effect levels (NOEL) for MeIQx on induction of glutathione S-transferase placental form (GST-P)-positive foci in the livers of F344 rats [8], [9]. GST-P-positive foci is a well-established preneoplastic lesion in the liver of rat and has been accepted as a marker for assessing carcinogenic potential in the liver [10]. Moreover, GST-P-positive foci in the liver has been suggested to be a useful end-point marker in assessment of carcinogenic effects of environmentally relevant concentrations of liver carcinogens [11]. More recently, we found that low doses of MeIQx did not increase mutation frequencies in rat livers and the dose–response curve for mutation frequency is nonlinear in an in vivo mutagenicity assay using male Big Blue rats with genetic background of F344 [12]. These findings argue against the linear no-threshold risk assessment model for genotoxic carcinogens and indicate that there is a practical threshold for hepatocarcinogenetic effects of MeIQx.
Given susceptibility to hepatocarcinogenesis varies considerably among different strains of rat [13], strain differences may exist in the dose–response curve. All above studies on MeIQx were conducted in F344 rat and little is known about the effects of low doses of this carcinogen on other strain rats. The major purpose of the present study is to determine whether the NOELs for MeIQx on induction of GST-P-positive foci exist in BN rats. We also compared the susceptibility of BN and F344 rats to carcinogenetic effects of MeIQx.
Section snippets
Animals
One-hundred and eighty male BN rats and 180 male F344 rats, 20-days old, were obtained from Charles River Japan, Inc. (Atsugi, Kanagawa, Japan). The animals were housed in polycarbonate cages (5/cage) in a room with a targeted temperature of 23±2 °C, humidity of 55±5%, and a 12 h light/dark cycle and ad libitum access to food and tap water.
Chemical and diets
MeIQx (purity, 99.9%) was purchased from Nard Institute, Nishinomiya, Japan. Basal diet (powdered MF) and MeIQx diets were prepared at Oriental Yeast Co.
General observations
All the rats survived in good condition until the scheduled sacrifice. No macroscopic lesions were noted in any tissue in any rats. As shown in Table 1, the body weights of BN groups were higher compared to F344 groups prior to the start of the study and continued to be higher throughout the experiment. Final body weights were significantly decreased in F344 rats administered 100 ppm MeIQx compared to controls. The similar decrease in body weight is also observed in the BN group administered 100
Discussion
The present study showed that low doses of MeIQx had no effects on induction of liver GST-P-positive foci in BN rats and therefore demonstrated the existence of NOEL for hepatocarcinogenicity of this genotoxic carcinogen. The same NOELs were also observed in F344 rats, although background level of GST-P positive foci is different in the two rat strains. Results for F344 rats are consistent with our previous work in which NOELs of MeIQx were suggested to be less than 10 ppm [8], [9]. These
Acknowledgements
This research was supported by a grant from the Japan Science and Technology Corporation, included in the Project of Core Research for Evolutional Science and Technology (CREST). The authors would like to acknowledge the encouragement of Dr Nobuyuki Ito (Emeritus Professor, Nagoya City University Medical School, Japan) and Dr Tomoyuki Kitagawa (Director, Cancer Institute, Tokyo, Japan).
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