Representation of endocrine organs in TCDD physiologically-based toxicokinetics (PBTK) models

Introduction

Endocrine disruptors (EDCs) are common environmental contaminants with concerning effects on multiple biological systems, notably the endocrine system [1]. Dioxins, a well-known class of EDCs, have been associated with thyroid and reproductive disorders in humans [2], [3]. Among them, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is most toxic, characterized by its persistence and bioaccumulation due to its lipophilic nature. Understanding TCDD toxicokinetics is crucial for assessing its health risks. Given its complex metabolism [4], physiologically-based toxicokinetics (PBTK)–an extension of physiology-based pharmacokinetic (PBPK) models–provide an in silico approach to estimate xenobiotics kinetics using in vitro and in vivo data. We reviewed the existing PBTK models for TCDD, with a particular focus on the inclusion of endocrine organs.

Methods

A systematic search was conducted in Pubmed, EMBASE and Google Scholar for PBTK models published up to October 2024. A total of 408 articles were identified, of which 31 met the inclusion criteria for review.

Results

The majority of PBTK models did not explicitly account for endocrine tissues. Instead, they broadly categorized organs as either slowly or richly perfused. Only a few models incorporated endocrine related structures, with the placenta included in three models and the mammary gland in two.

Conclusions

No PBTK models have independently assessed endocrine organs such as the thyroid, testis, or ovaries in the context of TCDD toxicokinetics. Given the mounting evidence of EDC-related health effect, integrating endocrine organs into PBTK models could enhance our understanding of EDC toxicokinetics and their adverse effects.