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Facing the Nuclear Threat: Thyroid Blocking Revisited
M. Luster, University Hospital, Marburg, Germany
Chr. Reiners, R. Schneider, H. Hänscheid
WHO Radiation Emergency Preparedness Assistance Network,
German Collaboration Center, University Hospital, Wuerzburg, Germany
Daily Release of I-131, Te-132 and Cs-137 During 10 Days after the Chernobyl Reactor Accident
Graphite-Fire
I-131:T1/2 8,1d
Te-132:T1/2 2,8m
Cs-137:T1/2 30a
Distribution of Radioactivity Europe April/May 1986
2011
25 Years After Chernobyl: Thyroid Doses in Infants
Thyroid Cancer in Young Girls and Females from Belarus after the Chernobyl Accident
2011
'Funny' Japanese Nuclear Boy Explains Disaster
Dose Limits
goal dose
• protection of goods 15 mSv / mission• protection of human life• avoidance of serious damage• urgent measurements
100 mSv / mission
• safe lives250 mSv / mission and
life time exposure
REAC/TS 2005
External Exposition
Penetrating irradiation
1 Gy
30 Gy
5 Gy
10 Gy
Subclinical
Hematological
Cerebro-vascular
Gastrointestinal
Mucocutaneous
How to react?
Intake ofiodine tabletsas protective measure in the event ofa severe accident in a nuclear powerplant– information leaflet
Age dependent Dosage
Suggestions for Intake
Bavarian Diet
Japanese Diet
Other Options?
Akashi M 2011
Iodine Kinetics of the Thyroid Follicular Epithelium
IodineBlocking
The Sodium(Natrium)-Iodide-Symporter (NIS)
I
Radioiodine Uptake
I
I
I
Potassium-Iodide(KI)-Blockade (appr. 100 mg)
KI
I
I
I
KI
KI
KI
KI
KI
KI
KI
Effectivity of KI-Blockade and Time of Exposure
Ilyin 1974, modified by Verger Thyroid 2001
Effectivity of Iodine Blockade and Use of Powdered Milk in Poland after Chernobyl 1986
Naumann und Wolff Am J Med 1993
1. Do we Have to Consider a Substantial Thyroid Cancer Risk in Adults after Exposure to Radioiodine?
Answers may be derived from:
- Modelling of age dependent thyroid doses
- Observed thyroid cancer cases after Hiroshima and Nagasaki
- Age dependent thyroid cancer risk in Russia after Chernobyl
Modelling: Age and Thyroid Doses after Inhalation or Ingestion
Zanzonico PB Health Phys. 2000
Age and Dose Related Risk-Coefficients for Thyroid Cancer
Thompson et al. Rad Res 1994
Thyroid Doses (Gy) and Relative Cancer Risk (RR) in Children from Russia after Chernobyl
Ivanov et al. Rad Prot Dosimetry 2012
Excess Relative Risk per Gy
Girls 0 - 17 years 6.54 P < 0.001Boys 0 - 17 years 2.24 P < 0.001
Adults > 18 years -1.47 n.s.
2. Does alimentary Iodine Supply influence Blockade with KI?
Answers may be derived from:
- Modelling of KI-blockade in relation to iodine supply
- Experiences with iodine goiter prophylaxis in Poland
- Experiments with KI-blockade in iodine-rich areas
Decrease of I-131 Uptake after Introduction of Goiter Prophylaxis with Iodized Salt in Poland
24h thyroid I-131 uptake
No Goiter Prophylaxis 45,7 + 6,6%
With KI 30 mg/kg Salt 27,3 + 10,4%
Huszno et al. J Endocrinol Invest 2003
Modelling Thyroid Uptake (%), Iodine Supply (250 vs. 50 ug/d) and Protective Effect of KI-Blockade with 100mg
Zanzonico & Becker Health Physics 2000
Protective Effect 40%
Protective Effect 17%
Protective Effect of 38 vs. 76 mg of KI in 8 Patients withGraves´Disease in Japan
Takamura et al. J Radiat Res 2004
Protective Effect 73.3% Protective Effect 79.5%
3. Are There Drugs Interacting with KI-Blockade?
Enhancing KI-Blockade:
- Other Iodine Containg Drugs, eg:
- Amiodarone
- X-Ray Contrast Media
- Antithyroid Drugs:
- Carbimazole, Methimazole
- Propyl-/Methyl-Thiouracil
- Perchlorate
- Thyroid Hormones
- Tyrosine-Kinase Inhibitors
Leung et al. Curr.Opin.Endocrinol.2012McCruden et al. Acta Endocrol.1985Reiners et al. Nuklearmedizn 1985Manavola et al. JCEM 2007
3. Are There Drugs Interacting with KI-Blockade?
Enhancing KI-Blockade:
- Other Iodine Containg Drugs, eg:
- Amiodarone
- X-Ray Contrast Media
- Antithyroid Drugs:
- Carbimazole, Methimazole
- Propyl-/Methyl-Thiouracil
- Perchlorate
- Thyroid Hormones
- Tyrosine-Kinase Inhibitors
Disturbing KI-Blockade:
- Iodine Containg Drugs:
if administered to late (> 24h)
- Lithium
Leung et al. Curr.Opin.Endocrinol.2012McCruden et al. Acta Endocrol.1985Reiners et al. Nuklearmedizn 1985Manavola et al. JCEM 2007
Dietlein et al Nuklearmedizin 2007Bogazzi et al. JCEM 1999
Dietlein et al. Nuklearmedizin 2007
If KI is administered more
than 48h after incorporation
of radioiodine,
the dose to the thyroid is
Increased by appr. 50%
Effectivity of KI-Blockade and Time of Exposure
4. How to Proceed in Emergencies with Repeated Releases of Radioiodine?
WHO KI-Guideline (update 1999)
4. How to Proceed in Emergencies with Repeated Releases of Radioiodine?
Answers may be derived from:
- Experimental data by the Wuerzburg group 2011
- Experimental Data of LA Ilyin et al. 1974
4. How to Proceed in Emergencies with Repeated Releases of Radioiodine?
Disappearance of the Protective Effect of a Single Dose of KI
> 40 years(n = 15)
< 25 years(n = 20)
Haenscheid et al. JCEM 2011
4. How to Proceed in Emergencies with Repeated Releases of Radioiodine?
Different daily doses of KI and protective effect
Ilyin et al. Atomizdat Moscow 1972
4. How to Proceed in Emergencies with Repeated Releases of Radioiodine?
- Strictly follow general recommendations:
> sheltering, evacuation, ban of contaminated
milk or food
- If recommended by the authorities, repeat taking KI-tablets
- Strictly follow recommendations for specific check-ups later on:
> especially in newborns, young children and in case of complaints
5. Which Side Effects of KI-Blocking have to be Taken into Consideration?
Answers may be derived from:
- General experiences with iodine containing drugs
- Experiences with KI-Blockade after Chernobyl in Poland
- Recent literature review by L.Spallek
- Animal experiments in chimpanzees
5. Which Side Effects of KI-Blocking have to be Taken into Consideration?
Systematic Review by Spallek et al. 2011:
- 14 articles relevant to the topic (mostly surveys, ecological and intervention studies)
- Only one study from Poland about KI-Blockade after Chernobyl directly addressing this question (Nauman & Wolff 1993)
- Overall :- No severe adverse reactions to KI in the general public- Evidence however is weak
Possible Side Effects of Potassium Iodide (KI)
Iodine Hypersensitivity
- True allergy against iodide: exanthema, edema,
sore throat, snuff, swelling of salivary glands, fever
- Dermatitis herpetiformis Duhring
- Iododerma tuberosum
- Hypokomplementemic vasculitis
- Myotonia congenita
very rare
Akuelles zur (iod)blockade der Schilddrüse
Possible Side Effects of Potassium Iodide (KI)
Iodine Hypersensitivity- True allergy against iodide: exanthema, edema,
sore throat, snuff, swelling of salivary glands, fever- Dermatitis herpetiformis Duhring- Iododerma tuberosum- Hypocomplementemic vasculitis- Myotonia congenita
Worsening of Preexisting Thyroid Disease- Elderly: thyrotoxicosis in patients with nodular goiter- Newborns and Infants: hypothyroidism if iodide is
administered in large doses
very rare
relativelyfrequent
Mazzaferri NEJM 1993
Detection of Thyroid Nodules
P re v
alen
c e (
%)
0 age (years)
Autopsy or ultrasound
Palpation
70
0
10
20
30
40
50
60
0 10 20 30 40 50 60 70 80 90
Prevalence of Thyroid Nodules in Adults(n = 83.757)
18,8% presence of thyroid enlargement
Diffuse goiter
Nodular goiter
Nodules only
No pathological findings
23,1% presence of thyroid nodlues10,0%
8,8%
66,9%
14,3%
3,5 %
57,4 %
39,1 %
39,1%48,4%
9%
3,5%
Diffuse goiter
Nodular goiter
Nodules only
No pathological findings
Prevalence of Thyroid Nodules in the Elderly
Toxic Nodular Goiter
Thyroidal Side Effects of KI-Blockade in Poland after Chernobyl in Adults
Naumann and Wolff Am J Med 1993
⬆?
⬇
⬇
⬇
Thyroidal Side Effects of KI-Blockade in Poland after Chernobyl in Newborns
Naumann and Wolff Am J Med 1993
Transient increases of TSH in 0,37% of newborns who received KI on day
General Side Effects of Iodine Blockade in Poland after Chernobyl 1986
Naumann and Wolff Am J Med 1993
5. Which Side Effects of KI-Blocking have to be Taken into Consideration?
Animal experiments in pregnant chimpanzees:
- 9 chimpanzees, week 19 – 21 of pregnancy
- KI 0.5, 1.95 or 6.5 mg/kg of BW (1.95 equals 130 mg in a pregnant woman)
- 1.95 mg/kg daily was effective and without side effects for mother and
fetus even if administered up to 10 days
Noteboom et al. Rad Res 1997
5. Which Side Effects of KI-Blocking have to be Taken into Consideration?
Animal Experiments in Infant Chimpanzees:
- 8 chimpanzees, age 8 – 66 weeks (median 32 weeks)
- KI 0.5, 1.95 or 6.5 mg/kg of BW (1.95 appr. ½ of the recommended dose of 16 mg for
a newborn)
- 1.95 mg/kg was effective and without side effects the infants even if
administered up to 10 days
Noteboom et al. Rad Res 1997
6. Do we Have Alternatives to KI for Thyroid Blocking?
The answer is yes, but:
- KI-Blockade always has to be considered in the context of other
protective measures, e.g. sheltering, evacuation, ban of
contaminated milk or food
- Perchlorate is a real alternative for thyroid blocking (but has
certain side effects and contraindications)
- For special indications, recombinant TSH may be given as a
decorporating agent
Iodine Kinetics of the Thyroid Follicular Epithelium
IodineBlocking
PerchlorateBlocking
KI
Perchlorate
Own data:
Effectivity of Blockade and Time of Exposure
So … Interim Conclusions
1. The risk for thyroid cancer in adults after exposure to irradiation is
close to zero
2. Alimentary iodine deficiency decreases the protective effect of KI
blockade
3. A number of drugs enhance and few decrease KI blockade
4. In case of repeated release, daily doses of appr. 100 mg KI are
advisable
5. Theoretical side effects of KI should not stand against necessary KI
blockade
6. Perchlorate is an alternative for thyroid blocking
Reiners C, Schneider R, Radiat. Protect. Dosimetry 2013 in press
Potassium-Perchlorate (ClO4) –Blockade (appr. 1g)
KClO4
ClO4
I
I
I
ClO4
ClO4
ClO4
ClO4
ClO4
ClO4
Potassium-Perchlorate (ClO4) –Blockade (appr. 1g)
ClO4
58
Potassium-Perchlorate (ClO4) –Blockade (appr. 1 g)
KClO4
ClO4
I
I
I
ClO4
ClO4
ClO4
ClO4
ClO4
ClO4
Potassium-Perchlorate (ClO4) –Blockade (appr. 1g)
ClO4
Potassium-Perchlorate Study
Time of intervention
Number of volunteers
KI 100 mg - 24 7
KI 100 mg 2 7
KI 100 mg 8 7
KI 100 mg 24 7
KClO4 1 g 2 7
KClO4 1 g 8 7
KClO4 0,1 g 8 7
Hours after incorporation
Thyroid Dose Reduction by KI and Perchlorate
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25
I-123(measured)
I-131 (calculated)
Dos
e Re
ducti
on %
Time of Blockade relative to Incorporation [ h p.i.]
Measured: dose reduction for I-123
100 mg KI 0,1 g KClO4 1 g KCLO4
Dose Reduction by KI and KClO4
0
20
40
60
80
100
Dos
e Re
ducti
on %
+2h-24h
KI 100mg
+2h
KClO41 g 0,1 g
KClO41 g
Time of Medication relative to Incorporation [ h p.i.]
+8h +24h +8h
KI
Own data:
Effectivity of Blockade and Time of Exposure
KI
Perchlorate
Own data:
Effectivity of KI-Blockade and Time of Exposure
Principle of Stimulation with recombinant TSH
rhTSHstimulation
I-131
I-131
I-131
020406080
100120140160180200
0 1 2 3 4 5 6 7 8 9 10
Time (days)
2 x i.m. 3 x i.m.
TSH
(mU
/L)
Serum TSH after 2 or 3 times 0,9 mg rhTSH i.m.
Whole-Body-Scan 12 d p.a.
131I-Therapy of Metastases under rhTSH
102
103
104
0 1 2 3 4 5 6 7 8
effective halflife Teff = 3 d
Whole-Body Activity
Appl. of 5200 MBq I -131
uptake 33%
Time p.a. (days)
MBq
Calculated dose to femur metastases:1000 Gy
Luster et al. JCEM 2000
Iodine Kinetics of the Thyroid Follicular Epithelium
rhTSHStimulation
rhTSH Study
Time of intervention
Number of volunteers
KI 100 mg 8 7
KI 100 mg 24 7
rhTSH 0,9 mg 8 7
rhTSH 0,9mg 24 7
rhTSH 0,9 mg +Methimazole
8 7
rhTSH 0,9 mg +Methimazole
24 7
Hours after incorporation
TSH and fT4 after rhTSH 0,9 mg i.m. in volunteers
fT4TSHmU/L pmol/L
min p.i.
Stable Iodine Content by X-Ray Fluorescence after rhTSH
pmol/Lmin p.i.
rhTSH 24 h after incorporation
Thyroid LT4 plasma
Time (min) after rhTSH Medication
Iodi
ne C
onte
nt b
y XF
A (m
g)
Stable Iodine Content by X-Ray Fluorescence after rhTSH
pmol/L
rhTSH 24 h after incorporation
Time (min) after rhTSH Medication
Iodi
ne C
onte
nt b
y XF
A (m
g)
Dose Reduction by KI and rhTSH
0
20
40
60
80
100D
ose
Redu
ction
%
24 h p.i.8 h p.i.24 h p.i.8 h p.i.
100 mg KI
24 h p.i.8 h p.i.
rhTSH + Methimazole0,9 mg rhTSH
*
Time of Medication relative to Incorporation [ h p.i.]
*
Summary
KI is effective 24 h before and up to 8 h after incorporation of radioiodine.
After 24 h, KI should not be administered because it prolongs the effective half-life of radioiodine.
Similar effects can be achieved by Potassium Perchlorate in patients with hypersensitivity against KI.
Potassium Perchlorate ist cheap and easy to administer. As an alternative i.m. injection of rhTSH together with 3 x 30 mg
of Methimazole may deplete appr. 40% of radioiodine even more than 24 h after incorporation.
However, rhTSH is expensive and not approved for this indication.