Relationship: 443



Thyroidal Iodide, Decreased leads to T4 in serum, Decreased

Upstream event


Thyroidal Iodide, Decreased

Downstream event


T4 in serum, Decreased

Key Event Relationship Overview


AOPs Referencing Relationship


Taxonomic Applicability


Sex Applicability


Life Stage Applicability


How Does This Key Event Relationship Work


The body is not able to produce or make iodine, thus the diet is the only source of this element. The ingested iodine is absorbed through the intestine and transported into the plasma to reach the thyroid gland, where its organification occurs. The organification of iodide is a complex enzyme-dependent process whereby ultimately leads to the formation of the thyroid hormones (T4 and T3). The thyroid actively concentrates the circulating iodide through the basolateral membrane of the thyrocytes by the sodium/iodide symporter protein (NIS). The concentrated thyroid-iodine is oxidized in the follicular cells of the gland and consequently binds to tyrosines to form mono- or di-iodotyrosines (MIT and DIT respectively), being incorporated into thyroglobulin. If two di-iodotyrosine molecules couple together, the result is the formation of thyroxin (T4). If a di-iodotyrosine and a mono-iodotyrosine are coupled together, the result is the formation of tri-iodothyronine (T3). If sufficient inhibition of iodide uptake occurs, formation of thyroid hormones is depressed leading to lower levels of these hormones in the bloodstream.

Weight of Evidence


Biological Plausibility


The most important role of iodide in the body is the formation of the thyroid hormones (T3 and T4). The body of a healthy adult contains up to 20 mg of iodine, of which 70-80% is accumulated in the thyroid (Fisher and Oddie, 1969). In iodine sufficient areas, the adult thyroid absorbs 60-80 μg of iodide per day to maintain the thyroid homeostasis (Degroot, 1966). Inadequate amount of iodide results to deficient production of thyroid hormones, which consequently leads to an increase of TSH secretion and goiter, a state known as hypothyroidism (Delange, 2000; Wolff, 1998). It is widely accepted that chronic ID patients suffer from the devastating effects of hypothyroidism that are not limited to endemic goiter, but also neurological impairments in the fetus, neonate and infant. Some of the most serious neurologic impairments associated with thyroid dysfunction stemming from iodide deficiency have been documented in children born in regions of the world where ID is prevalent (WHO/UNICEF/ICCIDD, 2011; Glinoer, 2001; Zimmermann, 2008). Furthermore, many animal studies also support the notion that defects in iodine uptake are reflected in the decreased levels of serum T3 and T4 and the increased levels of TSH (Caldwell et al., 1995; Clewell et al., 2003; Yu et al., 2001).

Empirical Support for Linkage


Perchlorate is a well-known thyroid disrupting chemical and it is extremely important for the investigation of iodide uptake, as it is believed to act solely by competitively inhibiting the transfer of iodide into the thyroid gland (Wolff, 1998). Previous research on perchlorate and possible thyroid-related health effects has paid little attention to the other common environmental NIS inhibitors, thiocyanate and nitrate, mainly because the relative potency of it is 10-200 times that of thiocyanate, and nitrate respectively on a molar basis (Tonacchera et al. 2004). However a person’s exposure to both thiocyanate and nitrate from drinking water and food account for a larger proportion of iodine uptake inhibition than does perchlorate exposure (De Groef et al. 2006). Therefore, additional research on the other two NIS inhibitors is of great importance but still lacking.

Analyses of the NHANES 2001-2002 dataset showed that urinary perchlorate concentrations were negatively associated, in a dose-dependent way, with serum T4 and FT4 concentrations and positively associated with serum thyrotropin in women, but not in men, (Blount et al., 2006; Cao et al., 2010; Suh et al., 2013; Steinmaus et al., 2007), with the strongest associations in women with low iodine and high thiocyanate (Steinmaus et al. 2013).

Moreover, several animal studies have demonstrated an association between serum thyroid hormones concentration and perchlorate (Siglin et al., 2000; Caldwell et al., 1995; Argus research laboratories 2001; York et al., 2003).

Uncertainties or Inconsistencies


Human studies have used potassium perchlorate to study the perchlorate inhibition of thyroidal iodide uptake and the effects on thyroid homeostasis. These studies were mainly short-term exposure studies and they failed to predict the association between perchlorate and serum concentration of thyroid hormones (Greer et al., 2002; Brabant et al., 1992; Lawrence et al., 2001; 2001). Because humans have relatively large amount of iodinated thyroglobulin in the colloid of thyroid follicles they can produce thyroid hormones for up to several weeks, even in the absence of iodide uptake. Therefore the human studies with exposure durations of 2 weeks or less possibly cannot identify toxic effects that may occur for long exposure durations. Surprisingly, a 6-month exposure to perchlorate at doses up to 3 mg/d (low doses) had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg (Braverman et al., 2006). This study was limited by the small sample size, however it supports the notion that low dose perchlorate in the environment does not cause adverse effects in the thyroid.

Interestingly, in one of the studies that perchlorate was negatively associated with T4 that happened only in women with iodine <100 μg/L (Blount et al. 2006), suggesting that iodine levels must be sufficiently low for environmental levels of perchlorate and thiocyanate to overcome compensatory mechanisms that maintain thyroid hormone (Steinmaus et al. 2007) at least in adults. Finally, in vitro studies of NIS inhibitors indicate that perchlorate, thiocyanate and nitrate act additively to inhibit iodide uptake (Tonacchera et al. 2004), thus suggesting that these exposures should be considered in combination in order to obtain robust results, and that kind of studies are still lacking.

Quantitative Understanding of the Linkage


The results exerted from the various studies described above cannot be consolidated into a quantitative measurement of the relationship between the thyroidal iodide uptake and the TH concentration due to the significant variations in the study design. However, a few predicting models (PBPK) have been developed that are able to provide a quantitative estimation of the dose-response relationship between perchlorate exposure and iodide inhibition (Lumen et al., 2013; McLanahan et al., 2008).

Evidence Supporting Taxonomic Applicability


The connection between NIS inhibition and serum thyroid levels has been studied in rats and human, as described above, but also in zebrafish model (Schmidt et al., 2012). The kinetics for perchlorate inhibition of iodine uptake in humans and rats are extremely similar [U.S. Environmental Protection Agency (EPA) 2002], indicating the homologous nature of the initial toxic event. However, there are important quantitative differences between the two species which should be carefully considered when interpreting serum TH and TSH data of animal perchlorate exposure studies.



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