Aop: 152

AOP Title


Interference with thyroid serum binding protein transthyretin and subsequent adverse human neurodevelopmental toxicity

Short name:


Transthyretin interference



Erik R. Janus; M3 Technical & Regulatory Services; Shepherdstown, WV; <erik@mcubedservices.com>

Kristie Sullivan; Physicians Committee for Responsible Medicine; Washington, DC; <ksullivan@pcrm.org>

Katie Paul-Friedman; US Environmental Protection Agency; Research Triangle Park, NC

Mary Gilbert; National Health and Environmental Effects Research Laboratory; US Environmental Protection Agency; Research Triangle Park, NC; <gilbert.mary@epa.gov>

Kevin M. Crofton; National Center for Computational Toxicology; US Environmental Protection Agenc; Research Triangle Park, NC; <crofton.kevin@epa.gov>

Point of Contact


Erik Janus



  • Erik Janus



Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.41 Included in OECD Work Plan

This AOP was last modified on March 20, 2017 09:47


Revision dates for related pages

Page Revision Date/Time
Binding, Transthyretin in serum September 16, 2017 10:16
Displacement, Serum thyroxine (T4) from transthyretin December 17, 2016 17:03
Increased, Free serum thyroxine (T4) September 16, 2017 10:16
Increased, Uptake of thyroxine into tissue December 17, 2016 17:04
Increased, Clearance of thyroxine from tissues September 16, 2017 10:16
Thyroxine (T4) in serum, Decreased September 17, 2017 18:37
Thyroxine (T4) in neuronal tissue, Decreased September 17, 2017 17:11
Hippocampal gene expression, Altered September 17, 2017 17:14
Hippocampal anatomy, Altered September 16, 2017 10:14
Hippocampal Physiology, Altered September 17, 2017 17:17
Cognitive Function, Decreased April 16, 2017 13:45
Halogenated phenols March 09, 2017 23:55
Polychlorinated biphenyl November 29, 2016 18:42
Polychlorinated dibenzodioxins March 09, 2017 20:38
Polybrominated diphenyl ethers March 09, 2017 20:40
Isoflavones March 09, 2017 21:14
Perflourinated chemicals March 09, 2017 22:36
Phthalates March 09, 2017 22:37
Tetrabromobisphenol A March 10, 2017 00:10
Clonixin March 10, 2017 00:50
Meclofenamic acid March 10, 2017 00:51
2,6-dinitro-p-cresol March 10, 2017 00:53
Triclopyr March 10, 2017 00:59
2,2',4,4'-Tetrahydroxybenzophenone November 29, 2016 18:42



This AOP describes adverse neurodevelopemental effects that may result from xenobiotic interference with thyroid serum binding protein transthyretin (TTR). Binding of TTR by a xenobiotic (the MIE) during certain developmental windows may disrupt the normal neurodevelopment of mammals through a transient increase in free thyroxine (T4) levels, permitting increased tissue uptake of thyroid hormone (TH), followed by a decrease in both serum and neuronal tissue concentrations. Due to the highly conserved nature of the TTR protein, birds, reptiles, fish and amphibians can also express TTR and be impacted by interference by xeniobiotics. The adverse consequences of TH insufficiency depend both on the severity and developmental timing, indicating that exposure to thyroid toxicants may produce different effects at different developmental windows of exposure. This AOP discusses the potential for developmental TTR interference to adversely impact hippocampal anatomy, function, gene expression and, ultimately, cognitive function.

Background (optional)


Transthyretin is one of three ancient, highly conserved serum binding proteins that collectively act to transport thyroid hormone (TH) and thus help maintain normal homeostasis via modulation of the hypothalamic/pituitary/thyroid axis. In addition to TTR, albumin (ALB) and thyroxine-binding globulin (TBG) also serve to transport TH in serum and the relative contribution of each binding protein differs across species. In man, TBG has the greatest affinity for thyroxine (T4), followed by TTR and ALB shows the lowest affinity for T4 while prevalence in serum is the opposite, while in rat, TTR is the major serum transport protein (as rats lack TBG). Interference with TH serum binding proteins is one of several mechanisms through which xenobiotics and environmental contaminants can disrupt normal thyroid endocrine function ("thyroid disruptors") and development of this AOP is expected to contribute towards a fuller understanding of the mechanism of TTR interference and how it may be measured in vitro as part of a larger screening battery for thyroid toxicants.

Summary of the AOP




Molecular Initiating Event


Title Short name
Binding, Transthyretin in serum Binding, Transthyretin in serum

Key Events


Title Short name
Displacement, Serum thyroxine (T4) from transthyretin Displacement, Serum thyroxine (T4) from transthyretin
Increased, Free serum thyroxine (T4) Increased, Free serum thyroxine (T4)
Increased, Uptake of thyroxine into tissue Increased, Uptake of thyroxine into tissue
Increased, Clearance of thyroxine from tissues Increased, Clearance of thyroxine from tissues
Thyroxine (T4) in serum, Decreased T4 in serum, Decreased
Thyroxine (T4) in neuronal tissue, Decreased T4 in neuronal tissue, Decreased
Hippocampal gene expression, Altered Hippocampal gene expression, Altered
Hippocampal anatomy, Altered Hippocampal anatomy, Altered
Hippocampal Physiology, Altered Hippocampal Physiology, Altered

Adverse Outcome


Title Short name
Cognitive Function, Decreased Cognitive Function, Decreased

Relationships Between Two Key Events (Including MIEs and AOs)


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 organization to predicted outcomes at higher levels of organization 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 weight of evidence 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. Description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for assessment of the AOP (section 7). The modified Bradford Hill considerations of biological plausibility and empirical support can be evaluated with regard to the predictive relationships/associations between pairs of KEs as a basis for considering weight of evidence of KERs (Section 7). The plausibility of the relationship between two KEs with respect to current understanding of normal (i.e., unperturbed biology) can be evaluated. Concordance of empirical evidence (i.e., dose-response, temporal and incidence concordance) can also be assessed and is usually based on consideration of these relationships following exposure to specific stressors that are believed to initiate the pathway. For example, temporal concordance can be evaluated by considering whether each “upstream” KE precedes the next “downstream” KE in the series. For empirical evidence derived for a specific stressor, dose-response and incidence concordance can also be evaluated to determine whether the pattern of results supports the hypothesized KER – i.e., does KEupstream occur at equivalent or lower doses and/or with less frequency than KEdownstream. Consistencies or inconsistencies in supporting data across different biological contexts and/or multiple studies can also help define confidence in the KER. Therefore, the suggested subsections of the KER description included in the current template are intended to aid the user in collecting relevant information that will support evaluation of the level of confidence in each KER, which in turn contributes to the assessment of the weight of evidence of the AOP, overall (section 7). By convention, KERs may take one of two forms. They may refer specifically to direct linkage between a pair of KEs that are adjacent in an AOP. Alternatively, a KER may refer to indirect linkages between a pair of KEs for which the relationship is thought to run through another KE or a gap in current understanding (i.e., non-adjacent KEs in an AOP; represented as dashed arrows in Figure 3). It is not necessary to describe a KER for every possible binary pair of KEs that could be indirectly linked. However, the option to provide KER descriptions for indirect KERs is particularly useful within the AOP-Wiki, because empirical evidence supporting the linkages among KEs in an AOP (see below) may often skip steps. For example, some KE measurements may be fairly difficult to make, such that they are rarely made in routine studies. While there may be sufficient data to establish the KE as part of the AOP, much of the available weight of evidence may ignore or “leap over” that particular KE. Including indirect KER descriptions allows the weight of evidence for these indirect relationships to be readily described and linked to other AOPs. Additionally, it can aid the process of developing and expanding putative AOPs where initial 19 linkages may span significant knowledge-gaps which are later filled in with additional KEs as more information becomes available and/or targeted research is completed.


To add a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Add relationship.’ User will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. Select a Directness from the drop down menu. The fields “Evidence” and “Quantitative understanding” can be entered at the time of creation of the relationship, or can be added later. Upon selection of these options from their respective drop-down menus, click ‘Update Aop relationship.’ The new relationship should be listed on the AOP page.

To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Directness, Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update Aop relationship’ to update these fields and return to the AOP page.

Network View



Life Stage Applicability


Is the AOP specific to certain tissues, life stages / age classes? Indicate if there are critical life stages, where exposure must occur, to results in the final adverse effect. Or specify if there are key events along the pathway which are dependent on the life stage although the AOP is known to be initiated regardless of life stage. Indicate also if the AOP is associated also with age- or sex-dependence.


To add a life stage term to an AOP page, under “Life Stage Applicability” select ‘add life stage term.’ User will be directed to a page entitled “Add Life Stage to AOP.” This page will list the AOP name, with drop down menu options to select a Life Stage term and Evidence. Evidence can be left blank and added later.

To edit a life stage term on an AOP page, under “Life Stage Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Life Stage” where they can edit the Evidence field using the drop down menu. Clicking ‘Update Aop life stage’ will update the Evidence field and redirect the user back to the AOP page.

Taxonomic Applicability


Indicate the relevant domain of applicability in terms of taxa.


To add a taxonomic term to an AOP page, under “Taxonomic Applicability” select ‘add taxonomic term.’ User will be directed to a page entitled “Adding Taxonomic Term to AOP.” The user can search for and select an existing term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, click ‘Request New Taxon Term’ to request a term from AOP-Wiki administrators. Click ‘Add taxonomic term’ to add this term to the AOP page. Evidence can be left blank and added later.

To edit a taxonomic term on an AOP page, under “Taxonomic Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Taxonomic Term” where they can edit the Evidence field using the drop down menu. Clicking ‘Update taxonomic term’ will update the Evidence field and redirect the user back to the AOP page.

Sex Applicability


Graphical Representation


Click to download graphical representation template

Overall Assessment of the AOP


This section addresses the relevant domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and weight of evidence for the overall hypothesised AOP (i.e., including the MIE, KEs and AO) as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). It draws upon the evidence assembled for each KER as one of several components which contribute to relative confidence in supporting information for the entire hypothesised pathway. An important component in assessing confidence in supporting information as a basis to consider regulatory application of AOPs beyond that described in Section 6 is the essentiality of each of the key events as a component of the entire pathway. This is normally investigated in specifically-designed stop/reversibility studies or knockout models (i.e., those where a key event can be blocked or prevented). Assessment of the overall AOP also contributes to the identification of KEs for which confidence in the quantitative relationship with the AO is greatest (i.e., to facilitate determining the most sensitive predictor of the AO).


To edit the “Overall Assessment of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Overall Assessment of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Overall Assessment of the AOP” section on the AOP page.

Domain of Applicability


The relevant domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Domain of applicability is informed by the “Description” and “Taxonomic Relevance” section of each KE description and the “Description of the KER” section of each KER description. The relevant domain of applicability of the AOP as a whole will most often be defined based on the most narrowly restricted of its KEs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the domain of applicability of the AOP as a whole would generally be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE descriptions, the rationale for defining the relevant domain of applicability of the overall AOP should be briefly summarised on the AOP page.


To edit the “Domain of Applicability” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Domain of Applicability” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Domain of Applicability” section on the AOP page.

Essentiality of the Key Events


Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

In vivo evidence for MIE

Kohrle et al (1989) added 10 μmol/L 3-methyl-4’,6-dihydroxy-3’,5-dibromo-flavone (EMD 21388) to pooled rat serum and measured displacement of [125I]-T4 from TTR. EMD21388 was synthesized using “molecular drug design” (and resembles T4) to help confirm previous findings that certain flavonoid deiodinase inhibitors also displaced thyroxine (T4) for TTR (or T3-binding prealbumin). Displacement of [125I] from TTR in rat serum was analyzed by gel electrophoresis (PAGE) and individual serum samples were assayed for T3 and T4 content by RIA and % free TH by equilibrium dialysis (lower limit of detectability 0.3 ug/dL for T4). There was a significant increase in % free T4 (0.031 to 0.124), which was dose-dependent and resulted in complete inhibition of [125I]-T4/TTR at 8-10 umol (radiolabeled TH were displaced primarily to albumin).

insert Fig 2 from Kohrle et al 1989

One to 4 hours following ip delivery of 2 μmol/100 g BW to euthyroid Sprague-Dawley rats (a dose that is 1000x higher than daily T4 production in rat), inhibition of [125I]-T4/TTR binding was observed. T4 decreased from 5.6 to 2.3 ug/dl after 1 hour and remained low while % free T4 increased from 0.035 to 0.091 and remained high; however, free T4 did not change. TSH decreased to very low values after 2 hours and increased slightly, despite no change in the free TH concentration (hypothyroid rats did not show changes in serum TSH following EMD 21388 administration). Lueprasitsakul et al (1990) performed a series of experiments with Sprague-Dawley rats using smaller doses of EMD 21388 (up to 2 μmol /100 g BW) and the same measurement methods (RIA, equilibrium dialysis). Administration of 2 μmol of EMD 21388 inhibited [125I]-T4/TTR binding within a few minutes, displacing [125I] to albumin to a greater degree of magnitude, due to slight differences in preparing the EMD 21388 solutions. Dose-dependent decreases in displacement were found with decreasing dose.

insert Figure 1 & Figure 2

Following a single dose of 2 μmol, a significant decrease was seen in total serum T4 after 10 minutes that persisted, % free T4 also increased immediately (peaked after 10 minutes) and stayed elevated and a significant increase in free T4 was observed within three minutes that stayed elevated for 60 minutes. Following a single dose of 0.3 μmol, decreased [125I]-T4/TTR binding was observed reaching a nadir after 10 minutes and slowly recovering over the 180-minute experiment. The % free T4 and serum free T4 both increased and returned to normal after 180 minutes as well while total serum T4 hit a nadir after 10 minutes and mostly recovered. Serum TSH decreased after 20 minutes, significantly at the nadir hit after 60 minutes.

Weight of Evidence Summary


This involves evaluation of the Overall AOP based on Relative Level of Confidence in the KERs, Essentiality of the KEs and Degree of Quantitative Understanding based on Annexes 1 and 2. Annex 1 (“Guidance for assessing relative level of confidence in the Overall AOP”) guides consideration of the weight of evidence or degree of confidence in the predictive relationship between pairs of KEs based on KER descriptions and support for essentiality of KEs. It is designed to facilitate assignment of categories of high, moderate or low against specific considerations for each a series of defined element based on current experience in assessing MOAs/AOPs. In addition to increasing consistency through delineation of defining questions for the elements and the nature of evidence associated with assignment to each of the categories, importantly, the objective of completion of Annex 1 is to transparently delineate the rationales for the assignment based on the specified considerations. While it is not necessary to repeat lengthy text which appears in earlier parts of the document, the entries for the rationales should explicitly express the reasoning for assignment to the categories, based on the considerations for high, moderate or low weight of evidence included in the columns for each of the relevant elements. 24 While the elements can be addressed separately for each of the KERs, the essentiality of the KEs within the AOP is considered collectively since their interdependence is often illustrated through prevention or augmentation of an earlier or later key event. Where it is not possible to experimentally assess the essentiality of the KEs within the AOP (i.e., there is no experimental model to prevent or augment the key events in the pathway), this should be noted. Identified limitations of the database to address the biological plausibility of the KERs, the essentiality of the KEs and empirical support for the KERs are influential in assigning the categories for degree of confidence (i.e., high, moderate or low). Consideration of the confidence in the overall AOP is based, then, on the extent of available experimental data on the essentiality of KEs and the collective consideration of the qualitative weight of evidence for each of the KERs, in the context of their interdependence leading to adverse effect in the overall AOP. Assessment of the overall AOP is summarized in the Network View, which represents the degree of confidence in the weight of evidence both for the rank ordered elements of essentiality of the key events and biological plausibility and empirical support for the interrelationships between KEs. The AOP-Wiki provides such a network graphic based on the information provided in the MIE, KE, AO, and KER tables. The Key Event Essentiality calls are used to determine the size of each key event node with larger sizes representing higher confidence for essentiality. The Weight of Evidence summary in the KER table is used to determine the width of the lines connecting the key events with thicker lines representing higher confidence.


To edit the “Weight of Evidence Summary” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Weight of Evidence Summary”  section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Weight of Evidence Summary” section on the AOP page.

Quantitative Considerations


The extent of quantitative understanding of the various KERs in the overall hypothesised AOP is also critical in consideration of potential regulatory application. For some applications (e.g. doseresponse analysis in in depth risk assessment), quantitative characterisation of downstream KERs may be essential while for others, quantitative understanding of upstream KERs may be important (e.g., QSAR modelling for category formation for testing). Because evidence that contributes to quantitative understanding of the KER is generally not mutually exclusive with the empirical support for the KER, evidence that contributes to quantitative understanding should generally be considered as part of the evaluation of the weight of evidence supporting the KER (see Annex 1, footnote b). General guidance on the degree of quantitative understanding that would be characterised as weak, moderate, or strong is provided in Annex 2.


To edit the “Quantitative Considerations” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Quantitative Considerations” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Quantitative Considerations” section on the AOP page.

Considerations for Potential Applications of the AOP (optional)


At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale. Detailing such considerations can aid the process of transforming narrative descriptions of AOPs into practical tools. In this context, it is necessarily beneficial to involve members of the regulatory risk assessment community on the development and assessment team. The Network view which is generated based on assessment of weight of evidence/degree of confidence in the hypothesized AOP taking into account the elements described in Section 7 provides a useful summary of relevant information as a basis to consider appropriate application in a regulatory context. Consideration of application needs then, to take into consideration the following rank ordered qualitative elements: Confidence in biological plausibility for each of the KERs Confidence in essentiality of the KEs Empirical support for each of the KERs and overall AOP The extent of weight of evidence/confidence in both these qualitative elements and that of the quantitative understanding for each of the KERs (e.g., is the MIE known, is quantitative understanding restricted to early or late key events) is also critical in determining appropriate application. For example, if the confidence and quantitative understanding of each KER in a hypothesised AOP are low and or low/moderate and the evidence for essentiality of KEs weak (Section 7), it might be considered as appropriate only for applications with less potential for impact (e.g., prioritisation, category formation for testing) versus those that have immediate implications potentially for risk management (e.g., in depth assessment). If confidence in quantitative understanding of late key events is high, this might be sufficient for an in depth assessment. The analysis supporting the Network view is also essential in identifying critical data gaps based on envisaged regulatory application.


To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page.



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