Evaluation of developmental neurotoxicity due to thyroid hormone disrupting effects of chemicals: Current status of efforts aimed at developing new evaluation methods

<p>Thyroid hormones (THs) are essential for brain development. Environmental chemicals with TH disruption are of regulatory concern for potential adverse effects on the developing brain. Although quantitative relationships between chemical-induced perinatal TH insufficiency and abnormal brain development have not been fully understood, several adverse outcome pathways (AOPs) associated with TH disruption have been identified, highlighting the need for efficient chemical safety screening and a reduction in animal testing. When using in vitro assays for regulatory purposes, there remains a challenge in application due to insufficient knowledge of TH signaling mechanisms during critical periods in target tissues, such as the developing brain. Indeed, many factors, including TH supply and chemical exposure, affect brain TH. We focused on a weight-of-evidence approach using an in vivo study, the Comparative Thyroid Assay (CTA) in rats, and began verifying the feasibility of a modified CTA by adding parameters (brain TH concentrations and brain heterotopia) but reducing the number of rats. The results indicate that the modified CTA has the potential to serve as an in vivo assay for identifying even mild perinatal TH disruptors. The modified CTA could also be instrumental in gathering data to construct a physiologically based pharmacokinetic model for the perinatal period, with the aim of employing New Approach Methodologies. This model could significantly contribute to our understanding of TH disruptions during critical stages of development and improve safeguards for human health.</p>