Upstream eventThyroidal Iodide, Decreased
T4 in serum, Decreased
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
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.
Evidence Supporting this KER
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).
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 and 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).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of 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.
Argus Research Laboratories. (2001). Hormone, thyroid and neurohistological effects of oral (drinking water) exposure to ammonium perchlorate in pregnant and lactating rats and in fetuses and nursing pups exposed to ammonium perchlorate during gestation or via material milk. Argus Research Laboratories, Inc. (as cited in U.S. EPA, 2002). Horsham,PA.
Blount BC, Pirkle JL, Osterloh JD, Valentin-Blasini L, Caldwell KL. (2006). Urinary perchlorate and thyroid hormone levels in adolescent and adult men and women living in the United States. Environ. Health Perspect. 114: 1865–1871.
Brabant G, Bergman P, Kirsch CM, Kohrle J, Hesch RD, Von Zur Muhlen A. (1992). Early adaptation of thyrotropin and thyroglobulin secretion to experimentally decreased iodine supply in man. Metabolism 41:1093 -1096.
Braverman, LE., Pearce EN, He X, Pino S, Seeley M, Beck, B, Magnani, B, Blount, BC, Firek A. (2006). The effect of six months daily low-dose perchlorate exposure on thyroid function in healthy volunteers. J Clin Endocrin Metab 91:2721-2724.
Caldwell DJ, King JH, Kinkead ER, Wolfe RE, Narayanan L, Mattie DR. (1995). Results of a fourteen day oral-dosing toxicity study of ammonium perchlorate. Dayton, Ohio: Wright-Patterson Air Force Base, Tri-Service Toxicology Consortium, Armstrong Laboratory.
Cao Y, Blount BC, Valentin-Blasini L, Bernbaum JC, Phillips TM, Rogan WJ. (2010). Goitrogenic anions, thyroid-stimulating hormone, and thyroid hormone in infants. Environ Health Perspect. 118:1332-1337.
Clewell RA, Merrill EA, Yu KO, Mahle DA, Sterner TR, Fisher JW, Gearhart JM. (2003). Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically-based pharmaco-kinetic modeling. Toxicol. Sci. 74(2):416-436.
De Groef B, Decallonne BR, Van der Geyten S, Darras VM, Bouillon R. (2006). Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Europ J Endocr. 155:17-25.
DeGroot LJ. (1966). Kinetic analysis of iodine metabolism. J Clin Endocrinol Metab. 26(2):149-173.
Delange F. (2000). The role of iodine in brain development. Proc Nutr Soc 59(1):75-79.
Fisher DA, Oddie TH. (1969). Thyroid iodine content and turnover in euthyroid subjects: validity of estimation of thyroid iodine accumulation from short-term clearance studies. J Clin Endocrinol Metab. 29(5):721-727.
Glinoer D. (2001). Pregnancy and iodine. Thyroid. 11(5):471-481.
Greer MA, Goodman G, Pleus RC, Greer SE. (2002). Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans. Environm Health Persp. 110: 927-937.
Lawrence JE, Lamm, SH, Pino S, Richman K, Braverman, LE. (2000). The effect of short-term low-dose perchlorate on various aspects of thyroid function. Thyroid 10: 659-63.
Lawrence J, Lamm S, Braverman, LE. (2001). Low dose perchlorate (3 mg daily) and thyroid function. Thyroid 11:295.
Lumen A, Mattie DR, Fischer WJ. (2013). Evaluation of perturbations in serum thyroid hormones during human pregnancy due to dietary iodide and perchlorate exposure using a biologically based dose-response model. Toxicol Sci 133: 320-341.
McLanahan ED, Andersen ME, Fisher JW. (2008). A biologically based dose-response model for dietary iodide and the hypothalamic-pituitary-thyroid axis in the adult rat: Evaluation of iodide deficiency. Toxicol. Sci. 102: 241–253.
Schmidt F, Schnurr S, Wolf R, Braunbeck T. (2012) Effect of the anti-thyroidal compound potassium-perchlorate on the thyroid system of the zebrafish. Aquat Toxicol. 109: 47-58
Siglin JC, Mattie DR, Dodd DE, Hildebrandt PK, Baker WH. (2000). A 90-day drinking water toxicity study in rats of the environmental contaminant ammonium perchlorate. Toxicol. Sci. 57(1):61-74.
Steinmaus C, Miller MD, Howd R. (2007). Impact of smoking and thiocyanate on perchlorate and thyroid hormone associations in the 2001-2002 national health and nutrition examination survey. Environ Health Perspect.115:1333-8.
Steinmaus C, Miller MD, Cushing L, Blount BC, Smith AH. (2013). Combined effects of perchlorate, thiocyanate, and iodine on thyroid function in the National Health and Nutrition Examination Survey 2007-08. Environ Res. 123:17-24.
Suh M, Abraham L, Hixon JG, Proctor DM. (2013). The effects of perchlorate, nitrate and thiocyanate on free thyroxine for potentially sensitive subpopulations of the 2001-2002 and 2007-2008 National Health and Nutrition Examination Surveys. J Expo Sci Environ Epidemiol. (Epub ahead of print)
Tonacchera M, Pinchera A, Dimida A, Ferrarini E, Agretti P, Vitti P, Santini F, Crump K, Gibbs J. (2004). Relative potencies and additivity of perchlorate, thiocyanate, nitrate, and iodide on the inhibition of radioactive iodide uptake by the human sodium iodide symporter. Thyroid. 14: 1012-1019.
U.S. EPA (Environmental Protection Agency). (2002). Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization. External Review Draft. NCEA-1-0503. Washington, DC: Office of Research and Development, U.S. EPA.
WHO, UNICEF, and ICCIDD. (2001). Assessment of the Iodine Deficiency Disorders and Monitoring Their Elimination. A Guide for Programme Managers. (WHO/NHD/01.1), 2nd ed, pp. 1–107. World Health Organization, Geneva.
Wolff J. (1998). Perchlorate and the thyroid gland. Pharmacol Rev. 50: 89-105.
York RG, Funk KA, Girard MF, Mattie D, Strawson JE. Oral (drinking water) developmental toxicity study of ammonium perchlorate in Sprague-Dawley rats. Int J Toxicol. 22(6):453-64.
Yu KO, Todd PN, Young Sm, Mattie DR, Fisher JW, Narayanan L, et al. (2001). Effect of perchlorate on thyroidal uptake of iodide with corresponding hormonal changes. AFRL-HE-WP-TR-2000-0076. Dayton, OH: U.S. Air Force, Wright-Patterson Air Force Base, Air Force Research Laboratory.
Zimmermann MB. (2008). Research on iodine deficiency and goiter in the 19th and early 20th centuries. J Nutr. 138(11):2060-2063.