Development of an ex-vivo-in-silico framework for predicting maternal and breastfed-infant toxicokinetics

生命早期接触来自母乳的环境污染物是人类风险评估日益关注的问题。婴儿暴露于母乳环境污染物的负担在很大程度上是未知的，因为化学剂的水平没有在这个矩阵中进行常规评估。因此，我们目前确定母乳喂养妇女的环境污染物的可耐受日摄入量（建立安全接触阈值）的能力仍然有限。在大多数情况下，阈值是根据动物研究的推断来确定的，没有考虑到哺乳和污染物对哺乳婴儿的潜在转移。拟议的研究计划旨在开发一个集成的离体硅框架，以识别对哺乳婴儿构成风险的环境污染物。该项目将把母乳/血浆中污染物分配的离体分析与基于生理的计算机毒物动力学（PBTK）模型结合起来，对哺乳婴儿体内污染物暴露进行合理预测。PBTK模型代表了一个生物学相关的建模平台，它结合了化合物物理化学和人体解剖学/生理学的信息，以估计环境污染物暴露如何转化为内部组织暴露。拟议的框架将为风险评估人员提供一种合理的方法，以确定母乳喂养妇女对现有和新出现的环境污染物的接触阈值。

Early-life exposure to environmental contaminants from breast-milk is an increasing concern for human risk assessments. The burden of infant exposure to environmental contaminants from breast-milk are largely unknown as levels of chemical agents are not routinely evaluated in this matrix. As a result, our current ability to define tolerable daily intakes, which establish safe exposure thresholds, for environmental contaminants in breastfeeding women remains limited. In most cases, thresholds are defined based on extrapolation from animal studies without consideration for lactation and potential transfer of contaminants to nursing infants. The proposed program of study aims to develop an integrated ex-vivo-in-silico framework to identify environmental contaminants that pose a risk to nursing infants. The program will merge ex-vivo analyses of contaminant partitioning in breast-milk/plasma with in-silico physiologically-based toxicokinetic (PBTK) models to generate rational predictions of internal contaminant exposure nursing infant. PBTK models represent a biologically relevant modelling platform that incorporates information on compound physico-chemistry and human anatomy/physiology to estimate how environmental contaminant exposure translates to internal tissue exposure. The proposed framework will provide risk assessors with a rational approach for establishing exposure thresholds in breastfeeding women for both existing as well emerging environmental contaminants.