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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
• Occupational
• NIS
• Environmental
– Neonatal
– Pediatric
– Adult
– Cancer
– Clinical studies
• Perchlorate
• Exposure ranges
Perchlorate (ClO4-) ion Characteristics
• A halogen Oxyanion:
ClO4-1
Perchlorate
One “extra” oxygen
atom
Tetrahydron
ClO3 –1
Chlorate
Most common form
ClO2-1
Chlorite
One less oxygen atom
ClO-1
Hypochlorite
Two fewer oxygen atoms
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)
• 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
The Sodium-Iodide Symporter
Iodine
Age Group
Recommended
I2 intake (μg/day)
Adults
Pregnant women
Lactating women
Adolescents
Children
Fetus in uteri,
Neonates and
150
175
200
150
90-120
90
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
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
Maternal
Fetal
Outcome
+
+
Good
+
-
-
+
Good if treated
early
May not be good
-
-
Bad
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 Exposure
Potential Risk
•
•
•
•
•
Pathologic
Therapeutic
Pharmacology
Occupational
Environmental
•
•
•
•
Neonatal
Pediatric
Adult
Cancer
Reported Deaths from Bone Marrow Toxicity
among Perchlorate-treated Thyrotoxicosis
Patients
Daily
Dosage
(mg/day)
Body Weight
Adjusted Daily
Dosage
(mg/kg/day)
Length of
Treatment for
each case
Hobson 1961
800
600
11
9
14 weeks
20 weeks
Fatal aplastic anemia
Johnson & Moore 1961
1000
600
14
9
3 months
1 month
Fatal aplastic anemia
Fawcett & Clark 1961
600
400
9
6
5 months
1-2 months
Fatal aplastic anemia
Krevans et al. 1962
800
600
450
11
9
6
2 weeks
2 months
2 months
Gjemdal 1963
600
400
9
6
3 months
1 month
Fatal aplastic anemia
Barzilai and Sheinfeld
1966
1000
14
2 months
Fatal aplastic anemia
1000
14
Few Months
Fatal agranulocytosis
Study
Effects
Fatal aplastic anemia
Therapeutic use of ClO4Indication
Dosage
Hyperthyroidism
600-900 mg/day
Hyperthyroidism in
pregnancy
600-1000 mg/day
Amiodarone induced
(treatment for resistant
tachyarryhthmias)
800-1000 mg/day then 16 months at lower doses
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
and
lead 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
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 0.01-34
mg/day
Perchlorate Exposure
• Environmental
•
•
•
•
Neonatal
Pediatric
Adult
Cancer
• Clinical Studies
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
• 1. CH data – no CH
(+ ClO4-) neonates compared
increase in exposed areas
with Reno (-)
Perchlorate exposure had no
• 2. T4 - Las Vegas (+ ClO4effect
15ppb) neonates
compared with Reno(-)
• 4.Chile – neonatal TSH
No ClO4- effect
(n=9,784). (100-120 ppb
compared to low exposures
• Brechner -Arizona
5-7 and <4ppb)
No differences found in TSH
levels
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 postexposure
• 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 ClO4drinking water level of 250 μg/L
Perchlorate dose-response in humans
exposed therapeutically, occupationally, in clinical
studies or environmentally via drinking water
Effect / endpoint
Fatal hemotoxicity
(aplastic anemia)
Non-fatal hemotoxicity
(blood-dyscrasias, including
agranulocytosis)
Therapeutic Effect Range for
Amiodarone treatment
Pharmacological Effect Range
(normalization of thyroid function
in hyperthyroid patients)
Calculated Safe Occupational
Average (BMDL)
Demonstrated Safe Occupational
Average ii
No-effect level for TSH elevation
in newborns iii (Environmental
Level 5-25 ppb)
i
Daily Dose
Body-Weight Adjusted
Daily Dose i
1000 - 2000 mg
15-30 mg/kg
600–1000mg
400 mg agranulocytosis
8.5-14 mg/kg
5.7 mg/kg
1000 mg start
followed by 100 mg
12.8 mg/kg
then 1.4 mg/kg
200-1000 mg
2.8 – 14 mg/kg
50 mg
0.7 mg/kg
Per shift average
2.5 mg
34 mg
Amount in 2L drinking water
200 μg
20 μg
Per shift average
0.036 mg/kg
0.48 mg/kg
2.9μg/kg
0.29μg/kg
ii No-effect level for tests of thyroid function in occupationally exposed
Based on a 70-kg adult
Exposed in utero via maternal consumption of drinking water
iii
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