The weight of evidence pro/contra classifying the process-related food contaminant (PRC) acrylamide (AA) as a genotoxic carcinogen is reviewed. Current dietary AA exposure estimates reflect margins of exposure (MOEs) < 500. Several arguments support the view that AA may not act as a genotoxic carcinogen, especially not at consumer-relevant exposure levels: Biotransformation of AA into genotoxic glycidamide (GA) in primary rat hepatocytes is markedly slower than detoxifying coupling to glutathione (GS). Repeated feeding of rats with AA containing foods, bringing about uptake of 100 µg/kg/day of AA, resulted in dose x time-related buildup of AA-hemoglobin (Hb) adducts, whereas GA-Hb adducts remained within the background. Since hepatic oxidative biotransformation of AA into GA was proven by simultaneous urinary mercapturic acid monitoring it can be concluded that at this nutritional intake level any GA formed in the liver from AA is quantitatively coupled to GS to be excreted as mercapturic acid in urine. In an oral single dose–response study in rats, AA induced DNA N⁷-GA-Gua adducts dose-dependently in the high dose range (> 100 µg/kg b w). At variance, in the dose range below 100 µg/kg b.w. down to levels of average consumers exposure, DNA N⁷ -Gua lesions were found only sporadically, without dose dependence, and at levels close to the lower bound of similar human background DNA N⁷-Gua lesions. No DNA damage was detected by the comet assay within this low dose range. GA is a very weak mutagen, known to predominantly induce DNA N⁷-GA-Gua adducts, especially in the lower dose range. There is consensus that DNA N⁷-GA-Gua adducts exhibit rather low mutagenic potency. The low mutagenic potential of GA has further been evidenced by comparison to preactivated forms of other process-related contaminants, such as N-Nitroso compounds or polycyclic aromatic hydrocarbons, potent food borne mutagens/carcinogens. Toxicogenomic studies provide no evidence supporting a genotoxic mode of action (MOA), rather indicate effects on calcium signalling and cytoskeletal functions in rodent target organs. Rodent carcinogenicity studies show induction of strain- and species-specific neoplasms, with MOAs not considered likely predictive for human cancer risk. In summary, the overall evidence clearly argues for a nongenotoxic/nonmutagenic MOA underlying the neoplastic effects of AA in rodents. In consequence, a tolerable intake level (TDI) may be defined, guided by mechanistic elucidation of key adverse effects and supported by biomarker-based dosimetry in experimental systems and humans.

审查了将与过程相关的食品污染物（PRC）丙烯酰胺（AA）列为遗传毒性致癌物的证据的正面/反面的依据。当前的膳食AA暴露估计值反映了暴露的边际（MOE）<500。一些论点支持以下观点：AA可能不会起到遗传毒性致癌物的作用，尤其是在与消费者无关的暴露水平下：AA生物转化为原发性的遗传毒性缩水甘油酰胺（GA）大鼠肝细胞的速度明显慢于与谷胱甘肽（GS）的解毒偶联。反复给大鼠喂食含AA的食物，使AA的摄入量达到100 µg / kg /天，导致剂量x时间相关的AA-血红蛋白（Hb）加合物的积累，而GA-Hb加合物仍保留在背景中。由于通过同时监测尿巯基酸证明了AA向GA的肝氧化生物转化，因此可以得出结论，在此营养摄入水平下，AA中在肝脏中形成的任何GA都定量地与GS偶联，以尿中的巯基酸形式排泄。在大鼠的口服单剂量反应研究中，AA诱导了DNAN ⁷ -GA-Gua在高剂量范围（> 100 µg / kg bw）中呈剂量依赖性加合。在变化范围内，在低于100 µg / kg bw的剂量范围内，直至平均消费者暴露水平，仅偶尔发现DNA N ⁷ -Gua损伤，无剂量依赖性，且水平接近相似的人类本底DNA N的下限。^7- Gua病变。在此低剂量范围内，彗星试验未检测到DNA损伤。GA是一种非常弱的诱变剂，已知主要诱导DNA N ⁷ -GA-Gua加合物，特别是在较低剂量范围内。有共识，DNA N ⁷-GA-Gua加合物表现出相当低的致突变性。与其他过程相关污染物（例如N）的预活化形式相比，GA的诱变潜力进一步得到了证明。-亚硝基化合物或多环芳烃，强效食源性诱变剂/致癌物。毒理基因组学研究没有证据支持基因毒性作用模式（MOA），而是表明了对啮齿动物靶器官中钙信号传导和细胞骨架功能的影响。啮齿类动物的致癌性研究表明，诱导了菌株和物种特异性肿瘤，而MOA并未被认为可能预示着人类癌症的风险。总之，总体证据清楚地证明了非遗传毒性/非诱变的MOA是AA在啮齿类动物中的肿瘤作用的基础。因此，在实验系统和人体中，可以通过关键性不良反应的机理阐明来指导耐受性摄入水平（TDI）并得到基于生物标记物的剂量测定法的支持。