mechanisms of thyroid toxicity
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Mechanisms of Thyroid Toxicity
Kevin M. CroftonNeurotoxicology DivisionNational Health and Environmental Effects LaboratoryUS Environmental Protection Agency Research Triangle Park NC
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Outline
1. Introduction to thyroid hormones2. Effects of perchlorate3. Effects of the disruption of thyroid hormones
Thyroid hyperplasia and neoplasiaDevelopmental abnormalities
4. Uncertainties
National Health and Environmental Effects Laboratory
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LiverUDPGTs
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
National Health and Environmental Effects Laboratory
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Iodine and the Thyroid Gland
I
-IT I
- organificationT4 & T3
THYROID GLAND
National Health and Environmental Effects Laboratory
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Thyroid Hormone Receptors and Thyroid Response Elements
Target Tissue Cell
T4-TTR
T4T3
deiodinase
Nucleus
T3 Response Element
RXR RAR TR
T3
AGGTCA.....
T3 Responsive Gene
RNA polymerase II
TATA....
National Health and Environmental Effects Laboratory
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Targets for Environmental Chemicals
■ Thyroid Gland ➨uptake process➨organification ➨release
■ Plasma Transport Proteins■ Tissue Deiodinases■ Hepatic Glucuronidation and Sulfation
National Health and Environmental Effects Laboratory
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In Vitro Thyrotoxicity of Perchlorate125Inhibition of I-Uptake by Perchlorate
Perchlorate Concentration, uM
0 1 10 100 1000
Iod
ine
influ
x,
pm
ol/m
g p
rote
in/m
in (
me
an
±SD
)
0
10
20
30
40
50
60
70
80
(Gerard et al., 1994)
National Health and Environmental Effects Laboratory
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14-Day In Vivo Perchlorate Study
Perchlorate dose (mg/kg/day)
0 0.125 0.5 1.25 2.5 5 12.5 25
TS
H C
on
cen
trat
ion
, pg
/dl
0
5
10
15
20
25
30
35
40
45
0 0.125 0.5 1.2 2.5 5 12.5 25
T3
Co
nce
ntr
atio
n, n
g/m
l
0
40
60
80
100
120
140
T4
Co
nce
ntr
atio
n, n
g/d
l
0
2
3
4
5
6
Male Female
0 0.125 0.5 1.2 2.5 5 12.5 25
T3 T4
TSH
(Caldwell et al., 1994)
National Health and Environmental Effects Laboratory
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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
National Health and Environmental Effects Laboratory
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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
National Health and Environmental Effects Laboratory
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Data Deficiencies
■ Long-term periodic exposures■ Perchlorate kinetics■ Thyroid hormone homeostasis
■ Effects during development
National Health and Environmental Effects Laboratory
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Uncertainties in Risk
1. Animal to Human Extrapolation
2. Age-Dependent Sensitivity
National Health and Environmental Effects Laboratory
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Uncertainties Due to Potential Species Differences
AdministeredDose
TargetDose
Effect
AdministeredDose
TargetDose
Effect
Rat
Human
? ?
ADME studies
Mechanistic / SensitivityStudies1. Adult2. Developmental
National Health and Environmental Effects Laboratory
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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
National Health and Environmental Effects Laboratory
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Do species differences exist? compare rodent and human sensitivitiesusing in vitro techniques
Resolving UncertaintiesMechanistic Studies
Perchlorate Concentration
0 1 10 100 1000
Iod
ine
Up
take
0
10
20
30
40
50
60
70
80
Human (?)
Rat
National Health and Environmental Effects Laboratory
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2. Age-Dependent SensitivityDevelopmental effects can be permanent.Is the developing organism more sensitive?
Yes - need to carefully characterizeNo - protection of maternal compartment
Uncertainties in Risk
National Health and Environmental Effects Laboratory
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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
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Resolving Uncertainty - Example
2. Age-Dependent Sensitivity
Determine relative sensitivity of fetal/postnatal thyroid versus adult
Determine relative sensitivity of rat versus human
National Health and Environmental Effects Laboratory
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National Health and Environmental Effects Laboratory
PBPK Model Schematic
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Summary
■ Facts:■ Perchlorate cause hypothyroidism
■ Uncertainties■ Animal to Human extrapolation■ Age-dependent senstivity
National Health and Environmental Effects Laboratory