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Relationship: 443


The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Thyroidal Iodide, Decreased leads to T4 in serum, Decreased

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

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

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

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).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

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.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

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.


List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

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.