PBPK model-based gender-specific risk assessment of N-nitrosodimethylamine (NDMA) using human biomonitoring data

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-08-03 DOI:10.1007/s00204-024-03828-w
Dong Wook Kang, Ju Hee Kim, Go-Wun Choi, Seok-jin Cho, Hea-Young Cho
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Abstract

Despite several screening levels for NDMA reported in water, soil, air, and drugs, the human risk assessment using biomonitoring concentrations has not been performed. In this study, gender-specific exposure guidance values were determined in humans, then biomonitoring measurements in healthy Korean subjects (32 men and 40 women) were compared to the exposure guidance values to evaluate the current exposure level to NDMA. For the human risk assessment of NDMA, the gender-specific physiologically based pharmacokinetic (PBPK) model was developed in humans using proper physiological parameters, partition coefficients, and biochemical parameters. Using the PBPK model, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty on the single model predictions. The PBPK modeling and Monte Carlo simulation allowed the estimation of the relationship between external dose and blood concentration for the risk assessment. The procedure for the human risk assessment was summarized as follows: (1) estimating a steady-state blood concentration (Cavg) corresponding to the daily no observed adverse effect level (NOAEL) administration in rats; (2) applying uncertainty factors (UFs) for deriving the human Cavg; (3) determining the exposure guidance values as screening criteria; (4) interpreting the human biomonitoring measurements by forward and reverse dosimetry approaches. Using the biomonitoring concentrations, current daily exposures to NDMA were estimated to be 3.95 μg/day/kg for men and 10.60 μg/day/kg for women, respectively. The result of the study could be used as a basis for implementing further risk management and regulatory decision-making for NDMA.

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利用人体生物监测数据,对 N-亚硝基二甲胺(NDMA)进行基于 PBPK 模型的性别风险评估
尽管报告了水、土壤、空气和药物中 NDMA 的若干筛选水平,但尚未使用生物监测浓度进行人体风险评估。本研究确定了不同性别的人体暴露指导值,然后将韩国健康受试者(32 名男性和 40 名女性)的生物监测测量值与暴露指导值进行比较,以评估当前的 NDMA 暴露水平。为了对 NDMA 进行人体风险评估,利用适当的生理参数、分配系数和生化参数建立了基于生理的人体药代动力学(PBPK)模型。利用 PBPK 模型,进行了蒙特卡罗模拟,以描述个体间变异性的大小和单一模型预测的不确定性。通过 PBPK 模型和蒙特卡罗模拟,可以估算出外部剂量和血液浓度之间的关系,从而进行风险评估。人体风险评估程序概述如下:(1) 估算与大鼠每日给药无不良影响水平(NOAEL)相对应的稳态血药浓度(Cavg);(2) 应用不确定性因子(UFs)得出人体 Cavg;(3) 确定作为筛选标准的暴露指导值;(4) 通过正向和反向剂量测定方法解释人体生物监测测量值。根据生物监测浓度,估计目前男性和女性每天摄入 NDMA 的分量分别为 3.95 微克/天/公斤和 10.60 微克/天/公斤。研究结果可作为进一步实施 NDMA 风险管理和监管决策的依据。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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