Thresholds for Genotoxic Carcinogens: Evidence from Mechanism‐Based Carcinogenicity Studies

Fukushima, Shoji; Wei, Min; Kakehashi, Anna; Wanibuchi, Hideki

doi:10.1002/9780470622728.ch8

Cited by 9 publications

(11 citation statements)

References 15 publications

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“…When the initiation activity of MeIQx was examined in a 2-stage carcinogenesis model using 850, 21-day-old male F344 rats with phenobarbital as promoter of hepatocarcinogenesis, GST-P+ foci in the rat livers were significantly increased in the 10 and 100 ppm dose groups, while no difference was found at doses of 1 ppm or less compared to non-treated controls (data not shown) [18,21].…”

Section: Hepatocarcinogenicity and Mutagenicity Of 2-amino-38-dimethmentioning

confidence: 98%

“…The effect of MeIQx exposure at different doses was investigated in 1145, 21-dayold male F344 rats. The chemical was administered in the diet at doses of 0, 0.001, 0.01, 0.1, 10 ppm (low dose groups) or 100 ppm (high dose group) for 16 and 32 weeks [17,18].The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 αg/man/day). In a 16-week experiment, the total numbers and areas of rat liver glutathione S-transferase placental form positive (GST-P + ) foci, which are preneoplastic lesions and the end point marker in rat hepatocarcinogenesis, were not changed in the 0.001-1 ppm MeIQx groups, but, at 10 ppm and 100 ppm a trend for an increase and a significant elevation were observed, respectively, as compared to non-treated controls ( Figure 1A and Table 1).…”

Section: Hepatocarcinogenicity and Mutagenicity Of 2-amino-38-dimethmentioning

confidence: 99%

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Threshold in Carcinogenicity of Genotoxic Carcinogens

Kakehashi

Fukushima²,

Wei³

et al. 2014

J Carcinog Mutagen

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Nowadays the idea of threshold in the carcinogenicity of chemical carcinogens has attracted interest in the field of carcinogenesis. With genotoxic agents there is considerable experimental evidence in support of the idea. Here, we report on the low dose carcinogenicity in rats observed with heterocyclic amines contained in cooked food, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), and contaminants of natural and manufactured food products, N-nitrosocompounds such as N-nitrosodiethylamine (DEN) and N-nitrosodimethylamine (DMN). The existence of a no-effect level for MeIQx carcinogenicity was confirmed in a medium-term rat liver bioassay. Treatment with increasing doses of MeIQx caused sequence of events to occur in the liver tissue: first, the induction of DNA-MeIQx adducts at low doses, then an increase of DNA 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation and lacI gene mutations, following by the development of preneoplastic lesions, glutathione S-transferase placental form positive (GST-P +) foci, at high doses. In another study, IQ was found to induce preneoplastic lesions in the rat liver at high doses, but lack any effect at low doses. Similarly, examination of carcinogenicity of a well-known colon genotoxic carcinogen PhIP have shown that application at low doses caused the formation of PhIP-DNA adducts, however, a surrogate marker of preneoplastic lesions in the colon, aberrant crypt foci, were detected only at high doses. In studies with N-nitrosocompounds, no GST-P+ foci in the rat livers was detected after the treatment at low doses, on the contrary, at high doses DEN and DMN induced their development. In conclusion, DNA-reactive genotoxic agents such as heterocyclic amines MeIQx, IQ and PhIP, and N-nitrosocompounds DEN and DMN were concluded to exert a threshold, at least practical, with respect to their carcinogenicity.

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Section: Hepatocarcinogenicity and Mutagenicity Of 2-amino-38-dimethmentioning

confidence: 98%

Section: Hepatocarcinogenicity and Mutagenicity Of 2-amino-38-dimethmentioning

confidence: 99%

Threshold in Carcinogenicity of Genotoxic Carcinogens

Kakehashi

Fukushima²,

Wei³

et al. 2014

J Carcinog Mutagen

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“…Therefore, the non-threshold theory for genotoxic carcinogens can be challenged in animal carcinogenic studies. To test this hypothesis, we have examined low dose carcinogenicities of the genotoxic carcinogens in rats over the past 10 years from the viewpoint of cancer risk assessment and management (2). In this symposium, we have presented and discussed the majorˆndings of our low-dose carcinogenicity studies.…”

Section: Introductionmentioning

confidence: 99%

Threshold for Genotoxic Carcinogens: The Central Concern in Carcinogenic Risk Assessment

Fukushima

Wei

Kakehashi

et al. 2012

Genes and Environment

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To verify scientiˆcally whether the non-threshold concept of genotoxic carcinogenicity is valid, we examined the hepatocarcinogenicities at low doses of three genotoxic carcinogens: 2-amino-3, 8 dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN) using a mediumterm rat hepatocarcinogenicity bioassay. We also examined alterations of molecular markers that cells typically acquire as they move through the initiation and promotion stages of carcinogenesis. We found that low doses of MeI-Qx induced formation of DNA-MeIQx adducts, somewhat higher doses caused elevation of oxidative DNA damage, at further higher doses gene mutations occurred; and the very highest dose of MeIQx induced formation of glutathione S-transferase placental form (GST-P) positive foci in the liver, a well-known preneoplastic lesion marker in rat hepatocarcinogenesis. Similarly, low doses of IQ and DEN had no eŠect on formation of GST-P positive foci in the rat liver. Furthermore, we demonstrated that concurrent treatment with combinations of sub-carcinogenic doses of MeIQx and DEN were not hepatocarcinogenic and the combined eŠects were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic eŠects, and synergetic eŠects were observed only in rats co-administered high doses of those 2 carcinogens. Theseˆndings demonstrated the existence of no eŠect levels for these genotoxic hepatocarcinogens, and suggested that there is a threshold, at least a practical threshold, that should be considered when evaluating the risk of exposure to genotoxic carcinogens.

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“…It is generally assumed that genotoxic carcinogens exert a non-threshold carcinogenic effect. This concept, however, is being challenged, as advancements in the understanding of the molecular mechanisms of carcinogenesis are being made and experimental evidence continues to accumulate showing that individual genotoxic carcinogens do not exert mutagenic or carcinogenic effects at low doses 1 , 2 , 3 , 4 , 5 , 6 . Given the probability that humans are exposed concurrently or sequentially to trace concentrations of multiple environmental carcinogens, examination of the effects of combinations of low doses of genotoxic carcinogens is an indispensable part of cancer risk assessment.…”

Section: Introductionmentioning

confidence: 99%

“…It also should be noted that the studies mentioned above focused mainly on the enhanced carcinogenic effects of combinations of multiple carcinogens and did not address the issue of threshold. Using various carcinogenesis models in different rat strains, we have demonstrated the existence of no effect levels for the hepatocarcinogenicity of 2-amino-3,8-dimethylimidazo[4,5- f ]quinoxaline (MeIQx), a genotoxic heterocyclic amine contained in seared fish and meat, and also for diethylnitrosamine (DEN), a genotoxic N -nitroso compound synthesized in the stomach through the reaction of secondary amines and nitrites in the diet 1 . The purposes of the present study were to evaluate the hepatocarcinogenicity of the concurrent treatment of MeIQx and DEN in rats and to determine whether no effect levels of combinations of these two genotoxic hepatocarcinogens exist.…”

Section: Introductionmentioning

confidence: 99%

Lack of Hepatocarcinogenicity of Combinations of Low Doses of 2-amino-3, 8-dimethylimidazo[4,5-<i>f</i>]quinoxaline and Diethylnitrosamine in Rats: Indication for the Existence of a Threshold for Genotoxic Carcinogens

et al. 2012

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The purposes of the present study were to evaluate the hepatocarcinogenicity of concurrent treatment of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and diethylnitrosamine (DEN) in rats and to determine whether no effect levels of combinations of these two different structural categories of genotoxic hepatocarcinogens exist. Two 16-week rat hepatocarcinogenesis assays were performed using a total of 790 male F344 rats. In experiment 1, we evaluated the effects of concurrent treatment of a subcarcinogenic dose of DEN on rat hepatocarcinogenesis induced by various doses of MeIQx. In experiment 2, we determined hepatocarcinogenicities of combinations of MeIQx and DEN at subcarcinogenic doses, low carcinogenic doses and high carcinogenic doses. Quantitative analyses of glutathione S-transferase placental form (GST-P)-positive foci, a preneoplastic lesion of the liver in rats, revealed that concurrent treatment with subcarcinogenic doses of DEN did not enhance MeIQx-induced rat hepatocarcinogenicity. We also found that concurrent treatment with combinations of subcarcinogenic doses of DEN and MeIQx was not hepatocarcinogenic, indicating that the combined effects of subcarcinogenic doses of DEN and MeIQx were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic effects. Synergetic effects were observed only in rats coadministered high carcinogenic doses of the 2 carcinogens. These results demonstrate the existence of no effect levels of combinations of these 2 genotoxic hepatocarcinogens, and provide new evidence supporting our idea that there is a threshold, at least a practical threshold, that should be considered when evaluating the risk of genotoxic carcinogens.

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Thresholds for Genotoxic Carcinogens: Evidence from Mechanism‐Based Carcinogenicity Studies

Cited by 9 publications

References 15 publications

Threshold in Carcinogenicity of Genotoxic Carcinogens

Threshold in Carcinogenicity of Genotoxic Carcinogens

Threshold for Genotoxic Carcinogens: The Central Concern in Carcinogenic Risk Assessment

Lack of Hepatocarcinogenicity of Combinations of Low Doses of 2-amino-3, 8-dimethylimidazo[4,5-<i>f</i>]quinoxaline and Diethylnitrosamine in Rats: Indication for the Existence of a Threshold for Genotoxic Carcinogens

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