This AOP describes how intracellular iodine deficits in thyroid follicular cells via chemical inhibition of sodium-iodide symporter (NIS) decrease thyroid hormone (TH) synthesis and cause delayed amphibian metamorphosis, or in extreme cases, arrests development. Amphibian metamorphosis is mediated by TH and successful completion of metamorphosis is generally required for organism survival. NIS is a critical transport protein that mediates iodine uptake into thyroid follicular cells making it available for thyroperoxidase (see TPO AOP) to catalyze its covalent bonding to tyrosine residues of thyroglobulin. TPO subsequently couples the iodinated tyrosines to form thyroxine (T4). Conversion of T4 to the active hormone, triiodothyronine (T3), is catalyzed by type I or II deiodinase enzymes (see DIO1 and DIO2 pAOPs) located within the peripheral organs and tissues, which then binds to thyroid receptor (TR). Activated TR then stimulates gene expression that drives the anatomical and physiological changes encompassed by the metamorphic process including limb emergence and development, lung development, gill and tail resorption, gut remodeling, metabolic profile changes in the liver, skin keratinization, etc. The model NIS inhibitor, perchlorate, has been tested in amphibian model species Xenopus laevis using in vivo study designs aiming to characterize temporal profiles of glandular hormone levels in addition to serum hormone levels and associated thyroid gland histopathology. Although there are only a few studies in amphibians that directly address NIS inhibition, these studies provide a strong weight of evidence supporting the specificity and essentiality of NIS inhibition leading to well-supported essential key events downstream.