1. Perchlorate The State of the Science Human Studies
Offie Porat Soldin, Ph.D.
Consultants in Epidemiology and Occupational Health, Inc.
Washington, D.C.

2. Outline Thyroid Occupational NIS Environmental Neonatal Perchlorate
Exposure ranges
Occupational
Environmental
Neonatal
Pediatric
Adult
Cancer
Clinical studies

3. Perchlorate (ClO4-) ion Characteristics
A halogen Oxyanion:
ClO Perchlorate
One “extra” oxygen atom
Tetrahydron
ClO3 – Chlorate
Most common form
ClO Chlorite
One less oxygen atom
ClO Hypochlorite
Two fewer oxygen atoms

4. Perchlorate (ClO4-) ion properties
High chemical stability. The reduction of Cl from a +7 oxidation state to –1 as a chloride requires energy or a catalyst and does not occur spontaneously
Hygroscopic. Highly water soluble
(AP is 20g/100g 25oC)
Exceedingly mobile in aqueous systems
Density nearly twice that of water
Can persist for decades due to kinetic barriers to its reactivity with other constituents

5. The Sodium-Iodide Symporter (NIS)
Controls the uptake of iodine by the thyroid
An intramembrane protein of 65kD
Co-transports iodide (I-) with two sodium (Na+) ions against an electrochemical gradient
Iodine thyroid/plasma gradient equals
25: 1 to 500: 1

6. The Sodium-Iodide Symporter

7. Iodine Age Group Recommended I2 intake (μg/day) Adults 150
Pregnant women
Lactating women
175
200
Adolescents
Children
90-120
Fetus in uteri, Neonates and infants 90

8. Effects of Iodine Deficiency Disorders
Adult
Goiter with its Complications Thyroid Deficiency Impaired Mental Function
Child
Goiter Thyroid Deficiency Impaired School Performance Retarded Physical Development
Neonate
Neonatal Goiter Brain Damage
Neurobehavioral
Fetus
Abortion Stillbirths Brain Damage - Cretinism

9. Pregnancy and Thyroid Function – The Mother
Iodine clearance by the kidney increases - increased glomerular filtration
Iodine and iodothyronines transferred to fetus
Women living in low iodine intake areas may develop iodine deficiency and enlarged thyroid
The hypothalamic-pituitary-thyroid axis functions normally in pregnant women with adequate iodine

10. Thyroid Adequacy Maternal Fetal Outcome + Good - Good if treated early
May not be good
Bad

11. Pregnancy and Thyroid Function – Fetus / Neonate I
Maternal hypothyroidism can be associated with neonatal defects (mental deficiency/ neurological defects/ low or normal IQs)
If infants have low T3 and T4 levels and elevated TSH levels, early appropriate treatment results in a normal intellect

12. Pregnancy and Thyroid Function – Fetus / Neonate II
NIS presence in mammary glands leads to secretion of iodine in milk, which is probably important for thyroid function in neonates
Prolactin stimulates NIS production which is inhibited by most anti-thyroidal agents, but not by perchlorate

13. ClO4- in water - Detection
1997 – Ion chromatography, assay sensitivity improved from 400ppb to 4 μg/L (4 ppb)
Public water supplies found to contain perchlorate ions: S California ppb; S Nevada ppb
Method modified for ClO4- detection in urine (LOD 500 ppb) and serum (LOD 50 ppb)
Electrospray ionization (ESI/MS/MS) (LOD 0.5 ppb) Less signal suppression by nitrate, bicarbonate and sulfate

14. Perchlorate Potential Exposure Potential Risk
Pathologic
Therapeutic
Pharmacology
Occupational
Environmental
Neonatal
Pediatric
Adult
Cancer

15. Reported Deaths from Bone Marrow Toxicity among Perchlorate-treated Thyrotoxicosis Patients
Study
Daily Dosage (mg/day)
Body Weight Adjusted Daily Dosage (mg/kg/day)
Length of
Treatment for
each case
Effects
Hobson 1961
800
600 11 9
14 weeks
20 weeks
Fatal aplastic anemia
Johnson & Moore 1961
1000 14
3 months
1 month
 Fatal aplastic anemia
Fawcett & Clark 1961
400 6
5 months
1-2 months
Krevans et al. 1962
450
2 weeks
2 months
Gjemdal 1963
Barzilai and Sheinfeld 1966
Few Months
Fatal agranulocytosis

16. Therapeutic use of ClO4-
Indication
Dosage
Hyperthyroidism
mg/day
Hyperthyroidism in pregnancy
mg/day
Amiodarone induced
(treatment for resistant tachyarryhthmias)
mg/day then 1-6 months at lower doses
Contains about 40% iodine by weight – I2/Amiodarone induced hypothyroidism or thyrotoxicosis

17. Perchlorate Pharmacology I
rapidly absorbed
excreted intact in the urine
half-life: 5-8 hr (humans)
95% recovered in urine over 72 hr
similar ionic size to iodide
competitive inhibitor of NIS

18. Perchlorate Pharmacology II
May not be translocated into the thyroid cell
Ki is estimated as μM
May inhibit iodide accumulation → goiter1 and
lead to hypothyroidism if iodine intake low < μg/day
May inhibit organic binding of iodine
by affecting thyroid peroxidase (not proven)
1 Toxic multinodular goiter (Plummer’s disease) refers to an enlarged multinodular
goiter commonly found in areas of iodine deficiency in which patients with
long-standing non-toxic goiter develop thyrotoxicosis

19. Perchlorate Diagnostic Use
The perchlorate discharge test - detect iodide organification defects (1000 mg)
Pertechnetate (Tc 99m) radiological studies to image brain, blood pool, localize the placenta. Pretreatment: mg ClO4- minimizes pertechnetate in thyroid, salivary glands and choroid plexus
Perchlorate is used to block the gastric uptake of Tc 99m in the investigation of GI bleeding
tracer radioiodine ± 500 μg stable iodide. 3 hr thyroid radioiodine uptake, followed by 1 gm of ClO4, radioiodine uptake 1 hr later. Decrease in the thyroid iodine 4 hrs > 15% of the 3 hr uptake is a positive test indicating an iodide organification defect

20. Perchlorate Epidemiological Studies Occupational Exposure
To determine exposure levels and potential health effects need to estimate a safe working level of perchlorate
Much higher than environmental
Exposure: inhalation, ingestion, or dermal contact
Significant systemic absorption likely because of the high aqueous solubility at body temperature
USA: No occupational standard for perchlorate
OSHA regulates perchlorate as a nuisance dust (limit of 15 mg/m3 (time-weighted average)
Safety concerns – it has explosive potential

21. Occupational Studies Gibbs et al. (1998) Nevada Cumulative exposure
Average lifetime dose: 38 mg/kg
No adverse effects on thyroid
Shift exposure
Inhaled dose: g/kg (ave 36 g/kg)
Lamm et al. (1999) Utah
Cross sectional
Individual exposure
Pre- post-shift urine
Group exposure
3 exposures & control group
Urine: 0.9 – 34 mg/shift (LOD=500 ppb)
Serum: 110 – 1600 ppb
(LOD 50 ppb)
No adverse effects on thyroid function mg/day

22. Perchlorate Exposure Environmental Clinical Studies Neonatal Pediatric
Adult
Cancer
Clinical Studies

23. Neonatal Studies Environmental exposure
Neonatal screening routine in most of the developed world
Congenital hypothyroidism (CH) treatable if caught early enough
3. Neonatal TSH - Las Vegas (+ ClO4-) neonates compared with Reno (-)
Perchlorate exposure had no effect
4.Chile – neonatal TSH (n=9,784). ( ppb compared to low exposures 5-7 and <4ppb)
No differences found in TSH levels
1. CH data – no CH increase in exposed areas
2. T4 - Las Vegas (+ ClO4- 15ppb) neonates compared with Reno(-)
No ClO4- effect
Brechner -Arizona

24. Pediatric Studies Environmental exposure
Children and adolescents at greatest risk for low I2
Crump et al. studied school-age children (n = 162)
ppb, 5-7ppb and < 4ppb ClO4- in their drinking water
No differences found in TSH, FT4 and goiter prevalence

25. Adult Studies Environmental exposure
Nevada Medicaid database ( )
Prevalence of thyroid diseases in areas exposed to ClO4- vs. areas unexposed
The prevalence rates of thyroid diseases was no greater in areas exposed to ClO4- in drinking water

26. Thyroid Cancer Studies Environmental exposure
Risk measures of thyroid cancer
Prevalence, Mortality, Incidence
All 3 measures showed no association with ClO4- exposure
ClO4- is non-mutagenic

27. Prospective Volunteer Studies I
900 mg/day ClO4- for 4 wks – FT4 decreased; thyroid gland not depleted of iodine (Brabant et al. 1992)
Iodine uptake inhibition studies (Lawrence et al. 2001)
Thyroid function studies and iodine-uptake studies (prior/ during 2 wk exposure (3 mg or 10 mg ClO4-)/ 2 wks post-exposure
No effect on thyroid function studies (T4, T3, FTI, thyroid hormone binding ratio & TSH)
10 mg/day dosage
38 % inhibition of iodine uptake
Serum ClO4- levels: 0.6 μg/ml (6 μM)
3 mg/day dosage
Serum ClO4- levels: below detection limit
A linear-log regression predicted a no-effect level of 2 mg/day
Linear-log extrapolation of the iodine uptake inhibition data would predict a no-effect level of about 2 mg/day.

28. Prospective Volunteer Studies II
Greer et al. (2000)
35 mg/day, 7 mg/day, 1.4 mg/day and 0.5 mg/day
Found a significant inhibition of iodine uptake
A linear-log regression predicted a no-effect level of 0.5 mg/day
0.5 mg/day had no effect on iodine uptake
The data indicated a no-effect on iodine uptake level equivalent to an environmental ClO4- drinking water level of 250 μg/L

29. Body-Weight Adjusted Daily Dose i
Perchlorate dose-response in humans exposed therapeutically, occupationally, in clinical studies or environmentally via drinking water
Effect / endpoint
Daily Dose
Body-Weight Adjusted Daily Dose i
Fatal hemotoxicity
(aplastic anemia) mg
15-30 mg/kg
Non-fatal hemotoxicity
(blood-dyscrasias, including agranulocytosis)
600–1000mg
400 mg agranulocytosis
mg/kg
5.7 mg/kg
Therapeutic Effect Range for Amiodarone treatment
1000 mg start
followed by 100 mg
12.8 mg/kg
then 1.4 mg/kg
Pharmacological Effect Range (normalization of thyroid function in hyperthyroid patients) mg
2.8 – 14 mg/kg
Calculated Safe Occupational Average (BMDL)
50 mg
0.7 mg/kg
Demonstrated Safe Occupational Average ii
Per shift average
2.5 mg
34 mg
0.036 mg/kg
0.48 mg/kg
No-effect level for TSH elevation in newborns iii (Environmental Level 5-25 ppb)
Amount in 2L drinking water
200 μg
20 μg
2.9μg/kg
0.29μg/kg
i Based on a 70-kg adult ii No-effect level for tests of thyroid function in occupationally exposed iii Exposed in utero via maternal consumption of drinking water

30. Model - Human Health and Perchlorate
Exposure Ranges

31. Summary I Thyroid - the critical effect organ of perchlorate toxicity
Perchlorate blocks iodide uptake by NIS
Assuming intake of 2 liters of water per day, the highest known level of ClO4- in public drinking water (24 μg/L) would yield a daily exposure of less than 50 μg/day – 700 times lower than the no effect level

32. Summary II
Absence of an observed effect on neonatal thyroid, thyroidal diseases, or thyroidal cancer in areas with ClO4- in drinking water is epidemiologically consistent with human toxicological and pharmacological observations

33. Summary III
Methods for measurement of ClO4- in urine, serum, solid matrix, and soil will need to be standardized in order to allow a better analysis and interpretation of data