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Threshold for genotoxic carcinogens: The central concern in carcinogenic risk assessment

机译：遗传毒性致癌物阈值：致癌风险评估中的核心问题

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To verify scientifically 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 medium-term 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 MeIQx 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 effect 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 effects were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic effects, and synergetic effects were observed only in rats co-administered high doses of those 2 carcinogens. These findings demonstrated the existence of no effect 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.
机译：为了科学地验证非阈值的遗传毒性致癌性概念是否有效，我们研究了低剂量的三种遗传毒性致癌物的肝致癌性：2-氨基-3、8二甲基咪唑并[4,5-f]喹喔啉（MeIQx），2-氨基使用中期大鼠肝致癌性生物测定法检测-3-甲基咪唑并[4,5-f]喹啉（IQ）和N-亚硝基二乙胺（DEN）。我们还检查了细胞通常在癌变的起始和促进阶段移动时获得的分子标记的变化。我们发现低剂量的MeIQx会诱导DNA-MeIQx加合物的形成，较高的剂量会引起氧化DNA损伤的增加，而在较高剂量下会发生基因突变。最高剂量的MeIQx会在肝脏中形成谷胱甘肽S-转移酶胎盘形式（GST-P）阳性灶，这是大鼠肝癌发生中众所周知的肿瘤前​​病变标志物。同样，低剂量的IQ和DEN对大鼠肝脏GST-P阳性灶的形成没有影响。此外，我们证明了同时使用亚致癌剂量的MeIQx和DEN进行联合治疗不会引起肝癌，并且联合作用既无累加作用，也无协同作用。此外，同时用低致癌剂量的这两种致癌物进行治疗没有显示出加和或协同作用，仅在高剂量同时使用这两种致癌物的大鼠中观察到了协同作用。这些发现表明，这些遗传毒性肝癌致癌因素没有作用水平，并建议在评估暴露于遗传毒性致癌物的风险时应考虑一个阈值，至少是一个实际阈值。

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