Facing the Nuclear Threat: Thyroid Blocking Revisited

Facing the Nuclear Threat: Thyroid Blocking Revisited

M. Luster, University Hospital, Marburg, Germany

Chr. Reiners, R. Schneider, H. HänscheidWHO 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 lives 250 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

http://edrv.endojournals.org/content/vol24/issue1/images/large/ef0130502001.jpeg

The Sodium(Natrium)-Iodide-Symporter (NIS)

I

Radioiodine Uptake

I

I

I

Potassium-Iodide(KI)-Blockade (appr. 100 mg)

KII

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?


- 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%


4. How to Proceed in Emergencies with Repeated Releases of Radioiodine?

WHO KI-Guideline (update 1999)



- Experimental data by the Wuerzburg group 2011

- Experimental Data of LA Ilyin et al. 1974


Disappearance of the Protective Effect of a Single Dose of KI

> 40 years(n = 15)

< 25 years(n = 20)

Haenscheid et al. JCEM 2011


Different daily doses of KI and protective effect

Ilyin et al. Atomizdat Moscow 1972


- 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?


- General experiences with iodine containing drugs

- Experiences with KI-Blockade after Chernobyl in Poland

- Recent literature review by L.Spallek

- Animal experiments in chimpanzees


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

Prev

alen

ce (

%)

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


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



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


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


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

ClO4I

I

I

ClO4

ClO4

ClO4

ClO4

ClO4

ClO4


ClO4

58

Potassium-Perchlorate (ClO4) –Blockade (appr. 1 g)

KClO4

ClO4I

I

I

ClO4

ClO4

ClO4

ClO4

ClO4

ClO4


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)

Dose

Red

uctio

n %

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

Dose

Red

uctio

n %

+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:


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


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

100Do

se R

educ

tion

%

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.

Thank you

[email protected]

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Facing the Nuclear Threat: Thyroid Blocking Revisited