Perchlorate The State of the Science Human Studies - PowerPoint PPT Presentation


PPT – Perchlorate The State of the Science Human Studies PowerPoint presentation | free to download - id: 961db-MjIyM


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation

Perchlorate The State of the Science Human Studies


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

Number of Views:112
Avg rating:3.0/5.0
Slides: 34
Provided by: fen5
Learn more at:


Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Perchlorate The State of the Science Human Studies

Perchlorate The State of the Science Human
  • Offie Porat Soldin, Ph.D.
  • Consultants in Epidemiology and Occupational
    Health, Inc.
  • Washington, D.C.
  • 12-12- 2001

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

Perchlorate (ClO4-) ion Characteristics
  • A halogen Oxyanion

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
  • 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

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
Effects of Iodine Deficiency Disorders

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
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
  • 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 Risk
  • Pathologic
  • Therapeutic
  • Pharmacology
  • Occupational
  • Environmental
  • Neonatal
  • Pediatric
  • Adult
  • Cancer

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

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
  • To determine exposure levels and potential health
    effects need to estimate a safe working level of
  • Much higher than environmental
  • Exposure inhalation, ingestion, or dermal
  • 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 (LOD500 ppb)
  • Serum 110 1600 ppb
  • (LOD 50 ppb)
  • No adverse effects on thyroid function 0.01-34

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 ( 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

Pediatric Studies Environmental exposure
  • Children and adolescents at greatest risk for low
  • Crump et al. studied school-age children (n
  • 100-120 ppb, 5-7ppb and lt 4ppb ClO4- in their
    drinking water
  • No differences found in TSH, FT4 and goiter

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

Thyroid Cancer Studies Environmental exposure
  • Risk measures of thyroid cancer
  • Prevalence, Mortality, Incidence
  • All 3 measures showed no association with ClO4-
  • 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 exposed iii Exposed in utero via
maternal consumption of drinking water
Model - Human Health and Perchlorate Exposure
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