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Perchlorate The State of the Science Human Studies

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Consultants in Epidemiology and Occupational Health, Inc. ... Pertechnetate (Tc 99m) radiological studies to image brain, blood pool, localize the placenta. ... – PowerPoint PPT presentation

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Title: Perchlorate The State of the Science Human Studies


1
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

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

3
Perchlorate (ClO4-) ion Characteristics
  • A halogen Oxyanion

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 solution _at_ 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
8
Effects of Iodine Deficiency Disorders

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
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 - 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

14
Perchlorate Potential ExposurePotential Risk
  • Pathologic
  • Therapeutic
  • Pharmacology
  • Occupational
  • Environmental
  • Neonatal
  • Pediatric
  • Adult
  • Cancer

15
Reported Deaths from Bone Marrow Toxicity among
Perchlorate-treated Thyrotoxicosis Patients
16
Therapeutic use of ClO4-
17
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

18
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 lt
    50-150 µg/day
  • May inhibit organic binding of iodine
  • by affecting thyroid peroxidase (not proven)
  • 1 Toxic multinodular goiter (Plummers 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 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

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 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 (LOD500 ppb)
  • Serum 110 1600 ppb
  • (LOD 50 ppb)
  • No adverse effects on thyroid function 0.01-34
    mg/day

22
Perchlorate Exposure
  • Environmental
  • 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 (n9,784). (100-120 ppb
    compared to low exposures 5-7 and lt4ppb)
  • 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)
  • 100-120 ppb, 5-7ppb and lt 4ppb ClO4- in their
    drinking water
  • No differences found in TSH, FT4 and goiter
    prevalence

25
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

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

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
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 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
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