# Presentation: 676975

## Mechanisms of Thyroid Toxicity

- <date/time>

**Mechanisms of Thyroid Toxicity**

**Kevin M. Crofton**
**Neurotoxicology Division**
**National Health and Environmental Effects Laboratory**
**US Environmental Protection Agency **
**Research Triangle Park NC**

## Slide 2

## Outline

- 1. Introduction to thyroid hormones
- 2. Effects of perchlorate
- 3. Effects of the disruption of thyroid hormones
- Thyroid hyperplasia and neoplasia
- Developmental abnormalities
- 4. Uncertainties

- National Health and Environmental Effects Laboratory

**Notes:**
Plot BMCs (in ppm) and BMDs (in mg/l) as functions of duration of exposure
Exposure-Effect:
BMC increases significantly with decreasing t
Slope of BMC curve is shallower than Haber's Law and
    steeper than constant C (no t)
Habers law overestimates the concentration of
    inhaled TCE necessary to affect signal detection at
    short times and thus underestimates the risk of
    effect for short, high-level exposures
Dose-Effect:
BMD is not significantly affected by t
 Slope of BMD curve is essentially flat: time is unimportant when the
  effect is predicted by the absorbed dose.  

## Liver

**Liver**

- UDPGTs

- T4-Gluc

- Biliary Excretion

**Hypothalamus-Pituitary-Thyroid-Liver Axis**

** **

**Plasma/Blood**

- Free-TH

- Bound-TH

- PA/TBG

**Hypothalamus**

**Pituitary**

**Thyroid**

**TRH**

**TSH**

- +

- +

- T3 & T4

- T3 & T4

**Tissue deiodinase**

- T4 > T3

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## Iodine and the Thyroid Gland

- I**-**

- IT

- I**-**

- organification

- T4 & T3

- THYROID GLAND

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##  Thyroid  Hormone Receptors and Thyroid Response Elements

- Target Tissue Cell

- T4-TTR

- T4

- T3

*deiodinase*

- Nucleus

- T3 Response Element

- RXR RAR

- AGGTCA.....

- T3 Responsive Gene

- RNA polymerase II

- TATA....

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## Targets for Environmental Chemicals

**Thyroid Gland **
**uptake process**
**organification **
**release**
**Plasma Transport Proteins**
**Tissue Deiodinases**
**Hepatic Glucuronidation and Sulfation**

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## In Vitro Thyrotoxicity of Perchlorate

**Perchlorate Concentration, **

***u***

**M**

**0**

**1**

**10**

**100**

**1000**

- Iodine influx,

- pmol/mg protein/min (mean±SD)

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

- (Gerard et al., 1994)

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## 14-Day In Vivo Perchlorate Study 

**Perchlorate dose (mg/kg/day)**

**TSH Concentration, pg/dl**

**T3 Concentration, ng/ml **

**0**

**40**

**60**

**80**

**100**

**120**

**140**

**T4 Concentration, ng/dl**

**Male **

**Female**

- T3

- T4

- TSH

- (Caldwell et al., 1994)

- National Health and Environmental Effects Laboratory

## Effect of TH disruption 

**Adult**
**Main effect of prolonged depression of TH is upregulation of TSH which leads to thyroid gland hyperplasia **
**Developmental**
**Main effect is the disruption of developmental processes**

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## Main Symptoms/Effects of Hypothyrodism

- Developmental
- delayed reflex ontogeny
- impaired fine motor skills
- deaf-mutism, spasticity
- gait disturbances
- mental retardation
- speech impairments
*transient disruption leads *
*to permanent effects*

- Adult
- run down, slow, depressed,
- sluggish, cold, tired
- dryness and brittleness of hair
- dry and itchy skin, constipation
- muscle cramps
- increased menstrual flow
*transient disruption leads to*
*transient effects*
-   *thyroid tumors in rodents

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## Data Deficiencies 

**Long-term periodic exposures**
**Perchlorate kinetics**
**Thyroid hormone homeostasis**
**Effects during development**

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## Uncertainties in Risk

- 1.  Animal to Human Extrapolation
- 2.  Age-Dependent Sensitivity

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## Uncertainties Due to 
Potential Species Differences

**Potential Species Differences**

- Administered
- Dose

- Target
- Dose

- Effect

*Administered*
*Dose*

*Target*
*Dose*

*Effect*

- Rat

*Human*

- ?

- ?

- ADME
- studies

- Mechanistic / Sensitivity
- Studies
- 1. Adult
- 2. Developmental

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## Mechanistic Studies

- Aid to quantitative interspecies extrapolation - basis to extend PBPK model
- Additional developmental studies to evaluate thyroid TH in fetal and post-natal periods
- Determine relative sensitivity of fetal/postnatal thyroid versus adult
- Determine relative sensitivity of rat versus human

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## Do species differences exist? 
compare rodent and human sensitivities
using in vitro techniques

- compare rodent and human sensitivities
- using in vitro techniques

**Resolving Uncertainties**
**Mechanistic Studies**

**Perchlorate Concentration**

**0**

**1**

**10**

**100**

**1000**

- Iodine Uptake

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

- Human (?)

- Rat

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## 2.  Age-Dependent Sensitivity
Developmental effects can be permanent.
Is the developing organism more sensitive?
Yes - need to carefully characterize
No - protection of maternal compartment 

- Developmental effects can be permanent.
- Is the developing organism more sensitive?
- Yes - need to carefully characterize
- No - protection of maternal compartment

**Uncertainties in Risk**

- National Health and Environmental Effects Laboratory

## ADME study

- Literature review of perchlorate discharge test
- Protocols proposed to evaluate perchlorate kinetics, iodine inhibition kinetics and thyroid hormone homeostasis
- Basis for development of physiologically-based pharmacokinetic (PBPK) model

- National Health and Environmental Effects Laboratory

## Resolving Uncertainty - Example

- 2.  Age-Dependent Sensitivity
- 	Determine relative sensitivity of fetal/postnatal thyroid versus adult
- 	Determine relative sensitivity of rat versus human

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## PBPK Model Schematic

**PBPK Model Schematic**

## Summary

- Facts:
- Perchlorate cause hypothyroidism
- Uncertainties
- Animal to Human extrapolation
- Age-dependent senstivity

- National Health and Environmental Effects Laboratory