Abstract

In Silico Framework to Account for the Interplay Between Different Mechanisms of Action for Multiple Thyroid Disruptors: A PBPK Model for Thiocyanate as a Case Study

Marie Willemin, Research Fellow, National Center for Toxicology Research, US Food and Drug administration (FDA)

Thiocyanate and perchlorate are environmental contaminants acting as thyroid disruptors. Both inhibit the active sodium/iodide symporter (NIS), which is responsible for the uptake of iodide into the thyroid. Thiocyanate additionally inhibits, and is also metabolized by, the thyroid peroxidase (TPO), an intra-thyroidal metabolic enzyme involved in the thyroid hormone synthesis. A quantitative global pathway model accounting for the key mechanisms of action in the target organ, in this case the thyroid, can be useful for determining of the non-additive effects of a multi-compound exposure, based on the individual dose-response data. In this study, we initiated the development of this framework for thyroid disruptors. A physiologically based pharmacokinetic (PBPK) model of thiocyanate was developed, with a mechanistic description of the intra-thyroidal kinetics involving NIS and TPO. The PBPK model was successfully developed in rats based on literature data, and then extrapolated to humans. Parameters describing the whole-body and intra-thyroidal kinetics of thiocyanate were estimated with a credible interval using a Bayesian context. The thiocyanate PBPK model will be linked to an iodide PBPK model, and can be used as an in silico toxicity prediction framework for studying further interaction effects with one or more xenobiotics that are thyroid active.