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首页> 外文会议>Annual conference of the International Society of Exposure Science >Biologically Based Dose Response modeling and its application in risk assessment: A case study of thyroid-active compounds
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Biologically Based Dose Response modeling and its application in risk assessment: A case study of thyroid-active compounds

机译：基于生物学的剂量反应模型及其在风险评估中的应用：以甲状腺活性化合物为例

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Computational approaches are increasingly being considered in risk assessment to guide regulatory decision-making. Biologically Based Dose Response (BBDR) model comprises of both physiologically based pharmacokinetic model (to link external exposure to internal dose) and mode-of-action based model (to link internal dose to corresponding response). Such integrated models allow for the use of available kinetic and dose-response data in animal models and non-pregnant adults and extrapolate to data-scarce sensitive sub-populations. A case study on the development and application of a BBDR pregnancy model for thyroid-active compounds, such as perchlorate and thiocyanate, will be discussed. A deterministic model for perchlorate was first developed in late-gestation pregnant women and extended to a population-based model. Reverse dosimetry approaches were implemented to utilize urinary biomarker data to reconstruct the daily iodine intake levels for late-gestation pregnant women in the U.S., which subsequently allowed for the identification of the prevalence of iodine inadequacy. Furthermore, probabilistic exposure-based risk assessment for perchlorate was also conducted. Our current efforts aim to continue the expansion of this computational pregnancy modeling framework to address the issue of co-exposure to mixtures of thyroid-active chemicals that reflects better real world exposure scenarios. Specifically, thiocyanate, a thyroid-disruptor with multiple modes of action, predominantly found in food is being evaluated in our ongoing work as a constituent of a ternary mixture. The recent findings in the modeling of thyroid-chemical mixtures and its implications in risk assessment will be summarized. The overall population-based risk assessment framework will provide regulatory agencies with a valuable and robust tool for the integrative assessment of the risks of adverse effects due to exposure to thyroid-active chemicals by a population of pregnant women.
机译：在风险评估中越来越多地考虑采用计算方法来指导监管决策。基于生物学的剂量反应（BBDR）模型包括基于生理的药代动力学模型（将外部暴露与内部剂量联系起来）和基于作用模式的模型（将内部剂量与相应反应联系起来）。这样的集成模型允许在动物模型和非怀孕的成年动物中使用可用的动力学和剂量反应数据，并推断出数据稀缺的敏感亚群。将讨论开发和应用针对甲状腺活性化合物（如高氯酸盐和硫氰酸盐）的BBDR怀孕模型的案例研究。首先在妊娠晚期孕妇中建立了高氯酸盐的确定性模型，并将其扩展到基于人群的模型。实施了反向剂量测定方法，以利用尿液生物标志物数据来重建美国晚期妊娠孕妇的每日碘摄入水平，随后可以确定碘不足的患病率。此外，还对高氯酸盐进行了基于概率暴露的风险评估。我们当前的工作旨在继续扩展此计算妊娠建模框架，以解决共同暴露于甲状腺活性化学物质混合物中的问题，这反映了更好的现实世界暴露场景。特别是，硫氰酸盐（一种在多种食物中起主要作用的甲状腺干扰物）主要在食物中被发现，在我们正在进行的工作中，正在评估其是否为三元混合物的组成部分。将总结甲状腺化学混合物模型的最新发现及其在风险评估中的意义。整个基于人群的风险评估框架将为监管机构提供一个有价值且强大的工具，以综合评估由于孕妇群体暴露于甲状腺活性化学物质而引起的不良影响的风险。

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