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

25 Years After Chernobyl: Thyroid Doses in Infants 2011

Thyroid Cancer in Young Girls and Females from Belarus after the Chernobyl Accident 2011

'Funny' Japanese Nuclear Boy Explains Disaster

250 mSv / mission and life time exposure 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 30 Gy 10 Gy 5 Gy 1 Gy Subclinical Hematological Cerebro- vascular Gastrointestinal Mucocutaneous Penetrating irradiation

How to react?

Intake of iodine tablets as protective measure in the event of a severe accident in a nuclear power plant – information leaflet

Age dependent Dosage

Suggestions for Intake

Other Options? Bavarian Diet Japanese Diet

Akashi M 2011

Iodine Kinetics of the Thyroid Follicular Epithelium Blocking

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

Radioiodine Uptake I I I

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

Effectivity of KI-Blockade and Time of Exposure Ilyin 1974, modified by Verger Thyroid 2001

Naumann und Wolff Am J Med 1993 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

Age and Thyroid Doses after Inhalation or Ingestion 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 Excess Relative Risk per Gy Girls 0 - 17 years 6.54 P < 0.001 Boys 0 - 17 years 2.24 P < 0.001 Adults > 18 years -1.47 n.s. Ivanov et al. Rad Prot Dosimetry 2012 26

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 27

No Goiter Prophylaxis 45,7 + 6,6% 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 28

Modelling Thyroid Uptake (%), Iodine Supply (250 vs. 50 ug/d) and Protective Effect of KI-Blockade with 100mg Protective Effect 40% Protective Effect 17% Zanzonico & Becker Health Physics 2000 29

Takamura et al. J Radiat Res 2004 Protective Effect of 38 vs. 76 mg of KI in 8 Patients with Graves´Disease in Japan Protective Effect 73.3% Protective Effect 79.5% Takamura et al. J Radiat Res 2004 30

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.2012 McCruden et al. Acta Endocrol.1985 Reiners et al. Nuklearmedizn 1985 Manavola et al. JCEM 2007 31

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.2012 McCruden et al. Acta Endocrol.1985 Reiners et al. Nuklearmedizn 1985 Manavola et al. JCEM 2007 Dietlein et al Nuklearmedizin 2007 Bogazzi et al. JCEM 1999 32

Effectivity of KI-Blockade and Time of Exposure If KI is administered more than 48h after incorporation of radioiodine, the dose to the thyroid is Increased by appr. 50% Dietlein et al. Nuklearmedizin 2007

4. How to Proceed in Emergencies with Repeated Releases of Radioiodine? WHO KI-Guideline (update 1999) 34

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 35

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 36

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 37

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 38

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 39

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 40

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 41

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 relatively frequent Akuelles zur (iod)blockade der Schilddrüse 42

Detection of Thyroid Nodules 70 Autopsy or ultrasound 60 50 Palpation Prevalence (%) 40 30 20 10 10 20 30 40 50 60 70 80 90 age (years) Mazzaferri NEJM 1993

Prevalence of Thyroid Nodules in Adults 18,8% presence of thyroid enlargement 23,1% presence of thyroid nodlues 10,0% 8,8% Diffuse goiter Nodular goiter Nodules only No pathological findings 14,3% 66,9% 44

Prevalence of Thyroid Nodules in the Elderly 3,5% 3,5 % 9% Diffuse goiter Nodular goiter Nodules only No pathological findings 39,1 % 57,4 % 48,4% 39,1%

Toxic Nodular Goiter

Thyroidal Side Effects of KI-Blockade in Poland after Chernobyl in Adults ⬆? ⬇ Naumann and Wolff Am J Med 1993 47

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 Naumann and Wolff Am J Med 1993 48

General Side Effects of Iodine Blockade in Poland after Chernobyl 1986 Naumann and Wolff Am J Med 1993 49

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 50

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 51

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 52

Iodine Kinetics of the Thyroid Follicular Epithelium Perchlorate Blocking Iodine Blocking 53

Effectivity of Blockade and Time of Exposure Own data: KI Perchlorate 54

So … Interim Conclusions The risk for thyroid cancer in adults after exposure to irradiation is close to zero Alimentary iodine deficiency decreases the protective effect of KI blockade A number of drugs enhance and few decrease KI blockade In case of repeated release, daily doses of appr. 100 mg KI are advisable Theoretical side effects of KI should not stand against necessary KI blockade Perchlorate is an alternative for thyroid blocking Reiners C, Schneider R, Radiat. Protect. Dosimetry 2013 in press 55

Potassium-Perchlorate (ClO4) –Blockade (appr. 1g) KClO4 56

Potassium-Perchlorate (ClO4) –Blockade (appr. 1g) 57

Potassium-Perchlorate (ClO4) –Blockade (appr. 1 g) KClO4 58 58

Potassium-Perchlorate (ClO4) –Blockade (appr. 1g) 59

Potassium-Perchlorate Study Time of intervention Number of volunteers KI 100 mg - 24 7 2 8 24 KClO4 1 g KClO4 0,1 g Hours after incorporation 60

Thyroid Dose Reduction by KI and Perchlorate 0% 20% 40% 60% 80% 100% Measured: dose reduction for I-123 100 mg KI 0,1 g KClO4 1 g KCLO4 Dose Reduction % I-131 (calculated) I-123 (measured) 5 10 15 20 25 Time of Blockade relative to Incorporation [ h p.i.] 61

Dose Reduction by KI and KClO4 100 KI 100mg KClO4 1 g 80 60 Dose Reduction % KClO4 1 g 0,1 g 40 20 -24h +2h +8h +24h +2h +8h Time of Medication relative to Incorporation [ h p.i.] 62

Effectivity of Blockade and Time of Exposure Own data: KI 63

Effectivity of KI-Blockade and Time of Exposure Own data: KI Perchlorate 64

Principle of Stimulation with recombinant TSH rhTSH stimulation 65

Serum TSH after 2 or 3 times 0,9 mg rhTSH i.m. 200 2 x i.m. 3 x i.m. 180 160 140 120 TSH (mU/L) 100 80 60 40 20 Slide 16. Pharmacokinetic modelling of the serum TSH levels over time for the two- and three-dose regimens are depicted. Maximal serum TSH concentrations were seen 24 hours after the final dose of rhTSH in both dosage regimens. As illustrated, TSH levels remained above 25 mU/L for 4 days with the two-dose regimen and 9 days with the three-dose regimen. The duration of TSH elevations (>25 mU/L) obtained with the three-dose regimen was, therefore, more comparable to that obtained with thyroid hormone withdrawal. The purpose of making this comparison was to determine whether a more sustained TSH level above 25 mU/L would increase 131I scan and thyroglobulin test sensitivities. 1 2 3 4 5 6 7 8 9 10 Time (days) 66

131I-Therapy of Metastases under rhTSH 102 103 104 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 Whole-Body-Scan 12 d p.a. Luster et al. JCEM 2000 67 3

Iodine Kinetics of the Thyroid Follicular Epithelium rhTSH Stimulation 68

rhTSH Study Time of intervention Number of volunteers KI 100 mg 8 7 24 rhTSH 0,9 mg rhTSH 0,9mg rhTSH 0,9 mg + Methimazole Hours after incorporation 69

TSH and fT4 after rhTSH 0,9 mg i.m. in volunteers pmol/L mU/L min p.i. 70

Stable Iodine Content by X-Ray Fluorescence after rhTSH rhTSH 24 h after incorporation Thyroid LT4 plasma Iodine Content by XFA (mg) Time (min) after rhTSH Medication min p.i. pmol/L 71

Stable Iodine Content by X-Ray Fluorescence after rhTSH rhTSH 24 h after incorporation Iodine Content by XFA (mg) pmol/L Time (min) after rhTSH Medication 72

* * Dose Reduction by KI and rhTSH 100 80 60 Dose Reduction % 40 20 100 mg KI 0,9 mg rhTSH rhTSH + Methimazole 80 60 Dose Reduction % * 40 * 20 8 h p.i. 24 h p.i. 8 h p.i. 24 h p.i. 8 h p.i. 24 h p.i. Time of Medication relative to Incorporation [ h p.i.] 73

Potassium Perchlorate ist cheap and easy to administer. 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. 74

Thank you markus.luster@med.uni-marburg.de