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Perchlorate The State of the Science Human Studies

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

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Perchlorate The State of the Science Human Studies

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

  3. Perchlorate (ClO4-) ionCharacteristics • 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 @ 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) • 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

  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. Study Daily Dosage (mg/day) Body Weight Adjusted Daily Dosage (mg/kg/day) Length of Treatment for each case Effects 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  Fatal aplastic anemia 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 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 < 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

  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 StudiesOccupational 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. 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 Occupational Studies

  22. Perchlorate Exposure • Environmental • Neonatal • Pediatric • Adult • Cancer • Clinical Studies

  23. 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 StudiesEnvironmental exposure • Neonatal screening routine in most of the developed world • Congenital hypothyroidism (CH) treatable if caught early enough

  24. Children and adolescents at greatest risk for low I2 Crump et al. studied school-age children (n = 162) 100-120 ppb, 5-7ppb and < 4ppbClO4- in their drinking water No differences found in TSH, FT4 and goiter prevalence Pediatric StudiesEnvironmental exposure

  25. 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 Adult StudiesEnvironmental exposure

  26. Thyroid Cancer StudiesEnvironmental 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. Body-Weight Adjusted Daily Dose i Effect / endpoint Daily Dose Fatal hemotoxicity (aplastic anemia) 1000 - 2000 mg 15-30 mg/kg Non-fatal hemotoxicity (blood-dyscrasias, including agranulocytosis) 600–1000mg 400 mg agranulocytosis 8.5-14 mg/kg 5.7 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 average 2.5 mg 34 mg Per shift average 0.036 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 μg 20 μg 2.9μg/kg 0.29μg/kg 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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