Perchlorate The State of the Science Human Studies Offie Porat Soldin, Ph.D. Consultants in Epidemiology and Occupational Health, Inc. Washington, D.C. 12-12- 2001
Perchlorate The State of the Science
Human Studies
Offie Porat Soldin, Ph.D.
Consultants in Epidemiology and Occupational Health, Inc.Washington, D.C.
12-12- 2001
Outline• Thyroid
• NIS
• Perchlorate
• Exposure ranges
• Occupational
• Environmental– Neonatal– Pediatric– Adult– Cancer– Clinical studies
Perchlorate (ClO4-) ion Characteristics
• A halogen Oxyanion:
Two fewer oxygen atomsClO-1 Hypochlorite
One less oxygen atomClO2-1 Chlorite
Most common formClO3 –1 Chlorate
One “extra” oxygen atom
Tetrahydron
ClOClO44-1-1 PerchloratePerchlorate
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 solution @ 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
The Sodium-Iodide Symporter (NIS)
• 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
• Controls the uptake of iodine by the thyroid
The Sodium-Iodide Symporter
Iodine
90 Fetus in uteri, Neonates and infants
90-120 Children
150 Adolescents
175
200
Pregnant women
Lactating women
150 Adults
Recommended
I2 intake (μg/day)
Age Group
Effects of Iodine Deficiency Disorders
AbortionStillbirthsBrain Damage - Cretinism
Fetus
Neonatal GoiterBrain Damage
Neurobehavioral
Neonate
GoiterThyroid DeficiencyImpaired School PerformanceRetarded Physical Development
Child
Goiter with its ComplicationsThyroid DeficiencyImpaired Mental Function
Adult
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
Thyroid Adequacy
Bad--
May not be good+-
Good if treated early-+
Good++
OutcomeFetalMaternal
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
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
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 - 5-8 ppb; S Nevada - 5-24 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
Perchlorate Potential ExposurePotential RiskPotential Risk
• PathologicPathologic
• TherapeuticTherapeutic• PharmacologyPharmacology
• OccupationalOccupational
• EnvironmentalEnvironmental• NeonatalNeonatal• PediatricPediatric
• AdultAdult• CancerCancer
StudyDaily
Dosage (mg/day)
Body Weight Adjusted Daily
Dosage (mg/kg/day)
Length ofTreatment for
each case
Effects
Hobson 1961 800800600
11119
14 weeks14 weeks20 weeks
Fatal aplastic anemia
Johnson & Moore 1961 10001000600
14149
3 months3 months1 month
Fatal aplastic anemia
Fawcett & Clark 1961 600600400
996
5 months5 months1-2 months
Fatal aplastic anemia
Krevans et al. 1962 800600600450
11996
2 weeks2 months2 months2 months
Fatal aplastic anemia
Gjemdal 1963 600600400
996
3 months3 months1 month
Fatal aplastic anemia
Barzilai and Sheinfeld 1966
10001000
1414
2 months2 months
Fatal aplastic anemia
10001000 1414 Few MonthsFew Months Fatal agranulocytosis
Reported Deaths from Bone Marrow Toxicity among Perchlorate-treated Thyrotoxicosis
Patients
Therapeutic use of ClO4-
800-1000 mg/day then 1-6 months at lower doses
Amiodarone induced
(treatment for resistant tachyarryhthmias)
600-1000 mg/dayHyperthyroidism in pregnancy
600-900 mg/dayHyperthyroidism
DosageIndication
Perchlorate Pharmacology I
• Pharmacology– 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
Perchlorate Pharmacology II
– May not be translocated into the thyroid cell
– Ki is estimated as 0.4-24 μM
– May inhibit iodide accumulation → goiter1 andlead to hypothyroidism if iodine intake low < 50-150 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
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: 200-400 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
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
Occupational Studies
• Gibbs et al. (1998) Nevada
• Cumulative exposure – Average lifetime dose: 38
mg/kg– No adverse effects on
thyroid
• Shift exposure
– Inhaled dose: 0.2-436 µg/kg (ave 36 µg/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 0.01-34 mg/day
Perchlorate Exposure
• Environmental• Neonatal• Pediatric
• Adult
• Cancer
• Clinical Studies
Neonatal Studies Environmental exposure
• 1. CH data – no CH increase in exposed areas
• 2. T4 - Las Vegas (+ ClO4-
15ppb) neonates compared with Reno(-) No ClO4
- effect
• Brechner -Arizona
• 3. Neonatal TSH - Las Vegas (+ ClO4
-) neonates compared with Reno (-)Perchlorate exposure had no effect
• 4.Chile – neonatal TSH (n=9,784). (100-120 ppb compared to low exposures 5-7 and <4ppb) No differences found in TSH levels
•Neonatal screening routine in most of the developed world•Congenital hypothyroidism (CH) treatable if caught early enough
Pediatric Studies Environmental exposure
• Children and adolescents at greatest risk for low I2
• Crump et al. studied school-age children (n = 162)
• 100-120 ppb, 5-7ppb and < 4ppb ClO4- in their
drinking water
• No differences found in TSH, FT4 and goiter prevalence
Adult Studies Environmental exposure
• Nevada Medicaid database (1997-1998)
• 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
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
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
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
Perchlorate dose-response in humans exposed therapeutically, occupationally, in clinical
studies or environmentally via drinking water
i Based on a 70-kg adult ii No-effect level for tests of thyroid function in occupationally exposediii Exposed in utero via maternal consumption of drinking water
Effect / endpoint
Daily Dose Body-Weight Adjusted Daily Dose i
Fatal hemotoxicity (aplastic anemia)
1000 - 2000 mg 15-30 mg/kg
Non-fatal hemotoxicity(blood-dyscrasias, including agranulocytosis)
600–1000mg400 mg agranulocytosis
8.5-14 mg/kg5.7 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)
200-1000 mg 2.8 – 14 mg/kg
Calculated Safe Occupational Average (BMDL) 50 mg 0.7 mg/kg
Demonstrated Safe Occupational Average ii
Per shift average2.5 mg34 mg
Per shift average0.036 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 μg20 μg
2.9μg/kg 0.29μg/kg
Model - Human Health and Perchlorate
Exposure Ranges
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
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
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