Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern , Erwin-Schroedinger-Strasse 52, 67663 Kaiserslautern, Germany.
Chem Res Toxicol. 2012 Feb 20;25(2):381-90. doi: 10.1021/tx200446z. Epub 2012 Jan 31.
Acrylamide (AA) is formed during the heating of food and is classified as a genotoxic carcinogen. The margin of exposure (MOE), representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be of concern. After ingestion, AA is converted by P450 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). We performed a dose-response study with AA in female Sprague-Dawley (SD) rats. AA was given orally in a single dosage of 0.1-10 000 μg/kg bw. The formation of urinary mercapturic acids and of N7-GA-Gua DNA adducts in liver, kidney, and lung was measured 16 h after application. A mean of 37.0 ± 11.5% of a given AA dose was found as mercapturic acids (MAs) in urine. MA excretion in urine of untreated controls indicated some background exposure from endogenous AA. N7-GA-Gua adduct formation was not detectable in any organ tested at 0.1 μg AA/kg bw. At a dose of 1 μg/kg bw, adducts were found in kidney (around 1 adduct/10(8) nucleotides) and lung (below 1 adduct/10(8) nucleotides) but not in liver. At 10, respectively, 100 μg/kg bw, adducts were found in all three organs, at levels close to those found at 1 μg AA/kg, covering a range of about 1-2 adducts/10(8) nucleotides. As compared to DNA adduct levels from electrophilic genotoxic agents of various origin found in human tissues, N7-GA-Gua adduct levels within the dose range of 0.1-100 μg AA/kg bw were at the low end of this human background. We propose to take the background level of DNA lesions in humans more into consideration when doing risk assessment of food-borne genotoxic carcinogens.
丙烯酰胺（AA）在加热食物的过程中形成，被归类为遗传毒性致癌物质。暴露界限（MOE）表示与大鼠 10%肿瘤发生率相关的基准剂量与估计的人类平均暴露量之间的距离，被认为是值得关注的。摄入后，AA 被 P450 转化为遗传毒性环氧化物丙烯醛（GA）。GA 形成 DNA 加合物，主要在鸟嘌呤的 N7 位（N7-GA-Gua）。我们在雌性 Sprague-Dawley（SD）大鼠中进行了 AA 的剂量反应研究。AA 以 0.1-10000μg/kg bw 的单次剂量经口给予。应用后 16 小时测量尿液中巯基尿酸和肝、肾和肺中 N7-GA-Gua DNA 加合物的形成。发现给予的 AA 剂量中有 37.0±11.5% 以巯基尿酸（MA）的形式出现在尿液中。未经处理的对照动物的尿液 MA 排泄表明存在一些内源性 AA 的背景暴露。在 0.1μg AA/kg bw 的剂量下，在测试的任何器官中均未检测到 N7-GA-Gua 加合物的形成。在 1μg/kg bw 的剂量下，加合物在肾脏（约 1 个加合物/108 个核苷酸）和肺（低于 1 个加合物/108 个核苷酸）中发现，但在肝脏中未发现。在 10、100μg/kg bw 时，加合物在所有三个器官中均有发现，水平接近 1μg AA/kg 时的水平，范围约为 1-2 个加合物/108 个核苷酸。与各种来源的亲电遗传毒性剂在人类组织中发现的 DNA 加合物水平相比，在 0.1-100μg AA/kg bw 的剂量范围内，N7-GA-Gua 加合物水平处于人类背景的低端。我们建议在对食物源遗传毒性致癌物质进行风险评估时，更多地考虑人类 DNA 损伤的背景水平。
