Biologically Based Dose Response modeling and its application in risk assessment: A case study of thyroid-active compounds

摘要

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.