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

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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.