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

开发用于预测母体和母乳喂养婴儿毒代动力学的离体计算机框架

• 批准号: RGPIN-2022-04406
• 负责人: Maharaj, Anil
• 金额: $ 1.89万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762007
• 关键词: Development; ex; vivo; silico; framework

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.

乳腺乳房中对环境污染物的早期暴露是人类风险评估的越来越多的关注点。婴儿乳腺暴露于环境污染物的负担在很大程度上是未知的，因为在此基质中未常规评估化学剂的水平。结果，对于母乳喂养女性中的环境污染物，我们目前定义可忍受的每日摄入量的能力（建立安全的暴露阈值）仍然有限。在大多数情况下，阈值是根据动物研究外推的推断而定义的，而无需考虑泌乳和污染物向护理婴儿的潜在转移。拟议的研究计划旨在开发一个综合的前体内硅框架，以确定对哺乳婴儿构成风险的环境污染物。该计划将合并胸间/血浆中污染物分配的外部分析与基于生理的毒素（PBTK）模型，以产生内部污染物暴露疗养的婴儿的合理预测。 PBTK模型代表了一个与生物学相关的建模平台，该平台结合了有关复合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于如何转化为内部组织暴露。拟议的框架将为风险评估者提供一种合理的方法，以建立母乳喂养女性的暴露阈值，以供现有的新兴环境污染物。