Comparative metabolism of 2-monochloropropane-1,3-diol (2-MCPD) and 3-monochloropropane-1,2-diol (3-MCPD) in rats and humans

2-单氯丙烷-1，3-二醇（2-MCPD）和3-单氯丙烷-1，2-二醇（3-MCPD）的脂肪酸酯是常见的热诱导食品污染物，其在胃肠道中有效水解以释放2/3-MCPD。在大鼠重复给药研究中，在肾脏（肾病和肥大）、睾丸（萎缩和动脉炎）和乳腺（腺体增生）中观察到3-MCPD暴露的最显著非肿瘤效应。此外，在大鼠2年生物测定中，3-MCPD增加了肾小管腺瘤和癌、间质细胞和乳腺增生和腺瘤的发生率。没有关于2-MCPD在动物中诱导的致癌作用和2/3-MCPD在人类中致癌作用的数据。国际癌症研究机构（IARC）已将3-MCPD列为对人类可能致癌的物质，而2/3-MCPD对大鼠的毒性和致癌性的分子机制概念还很有限。更好的理解取决于关于这两种化合物代谢的现有信息，这也可能有助于澄清在大鼠中观察到的一些毒性效应与人类健康的相关性。当前提案旨在比较阐明2/3-MCPD在大鼠和人体中的代谢。动物模型允许产生足够的量用于代谢物的系统表征。大鼠将接受2-或3-MCPD以及[13 C3] 2-MCPD或[13 C3] 3-MCPD单次经口给药。将通过制备色谱法分离尿液代谢物，并通过质谱法（MS）和13 C-核磁共振（NMR）光谱法进行表征。大鼠代谢产生的化合物数据将作为人尿液样本中排泄的2/3-MCPD代谢物表征的基础，这些样本是在对照暴露研究（先前进行）中收集的，榛子油含有相对较高量的结合2-MCPD（24.2 mg/kg）和3-MCPD（54.5 mg/kg）。2/3-MCPD代谢的信息是选择两种物质暴露的人体生物标志物的良好基础。我们建议开发的分析技术，用于定量的代谢物的2/3-MCPD在24小时尿液中，满足要求的灵敏度和特异性。选定的生物标志物将用于估计具有不同饮食习惯的研究参与者（杂食者、素食者和生食者;样本采集于2020年完成）的2/3-MCPD外部暴露量。总之，提供的2/3-MCPD代谢数据将有助于了解大鼠中的毒性效应以及可能与人类的相关性，并将支持确定个体中的人类暴露量和未来的风险管理建议。

Fatty acid esters of 2-monochloropropane-1,3-diol (2-MCPD) and 3-monochloropropane-1,2-diol (3-MCPD) are common heat-induced food contaminants, which are hydrolyzed efficiently in the gastrointestinal tract to release 2/3-MCPD. In repeated dose studies in rats, the most prominent non-neoplastic effects of 3-MCPD exposure were observed in kidney (nephropathy and hypertrophy), testes (atrophy and arteritis) and mammary gland (glandular hyperplasia). In addition, 3-MCPD increased incidences of renal tubular adenoma and carcinoma, hyperplasia and adenomas of the Leydig cells and of the mammary gland in 2-year bioassays in rats. There is no data on 2-MCPD-induced carcinogenic effects in animals and on 2/3-MCPD carcinogenic effects in humans. The International Agency for Research on Cancer (IARC) has classified 3-MCPD as possibly carcinogenic to humans.The concepts of the molecular mechanisms explaining the toxicity and carcinogenicity of 2/3-MCPD in rats are limited. A better understanding depends on the available information on the metabolism of both compounds, which may also help to clarify the relevance of some of the toxic effects observed in rats for human health. The current proposal aims at the comparative elucidation of the metabolism of 2/3-MCPD in rats and humans. The animal model allows generating sufficient amounts for a systematic characterization of metabolites. The rats will receive single oral doses of 2- or 3-MCPD and also of [13C3]2-MCPD or [13C3]3-MCPD. The urinary metabolites will be separated by preparative chromatography and characterized by mass spectrometry (MS) and 13C-nuclear magnetic resonance (NMR) spectroscopy. The data on the compounds resulting from rat metabolism will be the basis for the characterization of 2/3-MCPD metabolites excreted in human urine samples, collected in a controlled exposure study (conducted previously) with hazelnut oil containing relatively high amounts bound 2-MCPD (24.2 mg/kg) and 3-MCPD (54.5 mg/kg). The information of the 2/3-MCPD metabolism is a good basis for the choice of human biomarkers of exposure for both substances. We propose to develop analytical techniques for the quantification of metabolites of 2/3-MCPD in 24-h urine, which meet the requirements on sensitivity and specificity. The selected biomarkers will be used to estimate the external 2/3-MCPD exposure of study participants with distinct dietary habits (omnivores, vegans and raw food eaters; sample collection finished in 2020). In summary, the data provided on 2/3-MCPD metabolism will help to understand the toxic effects in rats and, possibly, the relevance for humans, and will support determining the human exposure in individuals and future recommendations on risk management.