Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
Arch Toxicol. 2017 Sep;91(9):3093-3108. doi: 10.1007/s00204-017-1941-x. Epub 2017 Mar 29.
Considering the rapid developments in food safety in the past decade in China, it is of importance to obtain insight into what extent safety and risk assessments of chemicals performed for the Caucasian population apply to the Chinese population. The aim of the present study was to determine physiologically based kinetic (PBK) modeling-based predictions for differences between Chinese and Caucasians in terms of metabolic bioactivation and detoxification of the food-borne genotoxic carcinogen estragole. The PBK models were defined based on kinetic constants for hepatic metabolism derived from in vitro incubations using liver fractions of the two ethnic groups, and used to evaluate the inter-ethnic differences in metabolic activation and detoxification of estragole. The models predicted that at realistic dietary intake levels, only 0.02% of the dose was converted to the ultimate carcinogenic metabolite 1'-sulfooxyestragole in Chinese subjects, whereas this amounted to 0.09% of the dose in Caucasian subjects. Detoxification of 1'-hydroxyestragole, mainly via conversion to 1'-oxoestragole, was similar within the two ethnic groups. The 4.5-fold variation in formation of the ultimate carcinogenic metabolite of estragole accompanied by similar rates of detoxification may indicate a lower risk of estragole for the Chinese population at similar levels of exposure. The study provides a proof of principle for how PBK modeling can identify differences in ethnic sensitivity and provide a more refined risk assessment for a specific ethnic group for a compound of concern.
考虑到过去十年中国食品安全的快速发展，了解化学物质的安全和风险评估在多大程度上适用于中国人群是很重要的。本研究的目的是确定基于生理的动力学（PBK）建模预测，以了解中国人和高加索人在食物源性遗传毒性致癌物茴香脑的代谢生物活化和解毒方面的差异。该 PBK 模型是基于来自两个种族的肝部分离物的体外孵育中获得的肝代谢动力学常数来定义的，并用于评估茴香脑代谢活化和解毒的种族间差异。该模型预测，在实际饮食摄入量水平下，只有 0.02%的剂量在中国人中转化为最终致癌代谢物 1'-磺酸氧基茴香脑，而在高加索人中这一比例为 0.09%。1'-羟基茴香脑的解毒主要通过转化为 1'-氧代茴香脑而相似。茴香脑最终致癌代谢物的形成差异 4.5 倍，同时解毒率相似，这可能表明中国人在类似暴露水平下对茴香脑的风险较低。该研究为 PBK 建模如何识别种族敏感性差异并为特定种族的特定化合物提供更精细的风险评估提供了一个原理证明。
