Perchlorate The State of the Science Human Studies

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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

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Outline

• Thyroid
• NIS
• Perchlorate
• Exposure ranges

• Occupational
• Environmental
• Neonatal
• Pediatric
• Adult
• Cancer
• Clinical studies

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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
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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

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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

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The Sodium-Iodide Symporter
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Iodine
Age Group Recommended I2 intake (µg/day)
Adults 150
Pregnant women Lactating women 175 200
Adolescents 150
Children 90-120
Fetus in uteri, Neonates and infants 90
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Effects of Iodine Deficiency Disorders
Adult Goiter with its ComplicationsThyroid DeficiencyImpaired Mental Function
Child GoiterThyroid DeficiencyImpaired School PerformanceRetarded Physical Development
Neonate Neonatal GoiterBrain Damage Neurobehavioral
Fetus AbortionStillbirthsBrain Damage - Cretinism

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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

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

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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

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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

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Perchlorate Potential ExposurePotential Risk

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

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Reported Deaths from Bone Marrow Toxicity among
Perchlorate-treated Thyrotoxicosis Patients
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Therapeutic use of ClO4-
Indication Dosage
Hyperthyroidism 600-900 mg/day
Hyperthyroidism in pregnancy 600-1000 mg/day
Amiodarone induced (treatment for resistant tachyarryhthmias) 800-1000 mg/day then 1-6 months at lower doses
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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

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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
•  

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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

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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

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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

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Perchlorate Exposure

• Environmental
• Neonatal
• Pediatric
• Adult
• Cancer

• Clinical Studies

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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

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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

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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

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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

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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

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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

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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
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Model - Human Health and Perchlorate Exposure
Ranges
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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

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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

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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