基于贝叶斯的苯并(α)芘PBPK模型优化与健康风险评估应用

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摘要应用基于生理的药代动力学(PBPK)模型预测苯并(α)芘(BaP)暴露的人体内部剂量,基于贝叶斯的马尔科夫链蒙特卡洛模拟(MCMC)方法对模型参数进行校准和优化,最后运用已优化的模型对BaP内暴露基准值进行推导.研究发现,基于贝叶斯的MCMC方法对模型后验参数校准后,模型精度明显提高,两个数据集验证结果显示残差平方和分别降低了72%和94%.PBPK模型以BaP和子代谢物3-羟基苯并(α)芘(3-OHBaP)的体内动力学过程为结构基础,模拟BaP体内浓度分布大小为脂肪>肾脏>皮肤>缓慢灌注组织>快速灌注组织>静脉血>肝脏;3-OHBaP体内浓度分布大小为肾脏>快速灌注组织>脂肪>肺>静脉血>缓慢灌注组织>肝脏>皮肤.敏感性分析显示,快速灌注组织-血分配系数对模型输出影响最大,灵敏度系数超过了200%;排泄系数影响最小,只有肾小球过滤率K_BR的灵敏度系数超过了1%.以美国国家环境保护局推荐的参考浓度2.0×10^-6mg/m³为外暴露安全基准值,基于PBPK模型推导了职业暴露的BaP生物监测当量(BE),结果显示BE值为0.405pmol/mol肌酐(尿液3-OHBaP平均浓度),为基于人体内暴露剂量水平进行定量健康风险评估奠定了基础.

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	孟祥晖
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	孙宇巍
	张明慧
	朱光灿
	沈亚琴
	柳慧芳

关键词 ：苯并(α)芘, 贝叶斯统计, 马尔科夫链蒙特卡洛方法(MCMC), 基于生理的药代动力学(PBPK)模型, 3-OHBaP, 生物监测当量

Abstract：The physiologically based pharmacokinetic(PBPK) model was used to predict the human internal dose of benzo(α)pyrene(BaP) exposure. The parameters of the model were optimized based on bayes statistics and Markov Chain Monte Carlo simulation (MCMC), and the optimized model was adopted to derive the reference value regarding the internal dose of BaP. It was found that the accuracy of the model was significantly improved after calibrating the posterior parameters by Monte Carlo simulation, and the validation results of two datasets showed that the sums of squared residuals were reduced by 72% and 94%. The PBPK model was based on the pharmacokinetic of BaP and its metabolite 3-hydroxybenzo(α)pyrene(3-OHBaP). The internal concentration distribution of BaP followed the order of fat>kidney>skin>slowly perfused tissue>richly perfused tissue>venous blood>liver, while that of 3-OHBaP was in the order of kidney>richly perfused tissue>fat>lung >venous blood >slowly perfused tissue> liver>skin. Besides, the sensitivity analysis indicated that the rich perfused tissue-blood distribution coefficients showed the strongest influence on the model output, which sensitivity coefficient exceeded 200%. While the coefficients related to excretion showed the weakest influence, and only sensitivity coefficient of glomerular filtration rate K_BR exceeded 1%. According to the reference concentration 2.0×10^-6mg/m³ recommended by U.S. Environmental Protection Agency, the biomonitoring equivalent of BaP was derived based on the optimized PBPK model. The results showed that the reference value for the occupational populations was 0.405pmol/mol creatinine (i.e., the mean concentration of 3-OHBaP in urine), which lays a foundation for the quantitative health risk assessment based on the human internal dose.

Key words： benzo(α)pyrene bayes statistics Markov Chain Monte Carlo(MCMC) physiologically based pharmacokinetic (PBPK) model 3-OHBaP biomonitoring equivalents

收稿日期: 2021-09-26

PACS:

X592

基金资助:国家重点研发计划项目(2021YFE0106600)

通讯作者: 王宏洋,高级工程师,wanghongyang_why@126.com;朱光灿,教授,gc-zhu@seu.edu.cn E-mail: wanghongyang_why@126.com;gc-zhu@seu.edu.cn

作者简介: 孟祥晖(1997-),男,四川绵阳人,硕士研究生,研究方向为PBPK模型和环境人体健康.发表论文1篇.

引用本文:

孟祥晖, 王宏洋, 孙宇巍, 张明慧, 朱光灿, 沈亚琴, 柳慧芳. 基于贝叶斯的苯并(α)芘PBPK模型优化与健康风险评估应用[J]. 中国环境科学, 2022, 42(5): 2370-2378. MENG Xiang-hui, WANG Hong-yang, SUN Yu-wei, ZHANG Ming-hui, ZHU Guang-can, SHEN Ya-qin, LIU Hui-fang. Optimization of benzo (α) pyrene PBPK model based on bayes and its application in health risk assessment. CHINA ENVIRONMENTAL SCIENCECE, 2022, 42(5): 2370-2378.

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http://www.zghjkx.com.cn/CN/ 或 http://www.zghjkx.com.cn/CN/Y2022/V42/I5/2370

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