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4711

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  • Contains about 40% iodine by weight – I 2 /Amiodarone induced hypothyroidism or thyrotoxicosis
  • tracer radioiodine ± 500 μ g stable iodide. 3 hr thyroid radioiodine uptake, followed by 1 gm of ClO 4 , radioiodine uptake 1 hr later. Decrease in the thyroid iodine uptake @ 4 hrs > 15% of the 3 hr uptake is a positive test indicating an iodide organification defect
  • Linear-log extrapolation of the iodine uptake inhibition data would predict a no-effect level of about 2 mg/day.
  • Transcript

    • 1. Perchlorate The State of the Science Human Studies <ul><li>Offie Porat Soldin, Ph.D. </li></ul><ul><li>Consultants in Epidemiology and Occupational Health, Inc. </li></ul><ul><li>Washington, D.C. </li></ul><ul><li>12-12- 2001 </li></ul>
    • 2. Outline <ul><li>Thyroid </li></ul><ul><li>NIS </li></ul><ul><li>Perchlorate </li></ul><ul><li>Exposure ranges </li></ul><ul><ul><ul><li>Occupational </li></ul></ul></ul><ul><ul><ul><li>Environmental </li></ul></ul></ul><ul><ul><ul><ul><li>Neonatal </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pediatric </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Adult </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cancer </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Clinical studies </li></ul></ul></ul></ul>
    • 3. Perchlorate (ClO 4 - ) ion Characteristics <ul><li>A halogen Oxyanion: </li></ul>Two fewer oxygen atoms ClO -1 Hypochlorite One less oxygen atom ClO 2 -1 Chlorite Most common form ClO 3 –1 Chlorate One “extra” oxygen atom Tetrahydron ClO 4 -1 Perchlorate
    • 4. Perchlorate (ClO 4 - ) ion properties <ul><li>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 </li></ul><ul><li>Hygroscopic. Highly water soluble </li></ul><ul><li>(AP is 20g/100g solution @ 25 o C) </li></ul><ul><li>Exceedingly mobile in aqueous systems </li></ul><ul><li>Density nearly twice that of water </li></ul><ul><li>Can persist for decades due to kinetic barriers to its reactivity with other constituents </li></ul>
    • 5. The Sodium-Iodide Symporter (NIS) <ul><li>An intramembrane protein of 65kD </li></ul><ul><li>Co-transports iodide (I - ) with two sodium (Na + ) ions against an electrochemical gradient </li></ul><ul><li>Iodine thyroid/plasma gradient equals </li></ul><ul><li>25: 1 to 500: 1 </li></ul><ul><ul><li>Controls the uptake of iodine by the thyroid </li></ul></ul>
    • 6. The Sodium-Iodide Symporter
    • 7. Iodine 90 Fetus in uteri, Neonates and infants 90-120 Children 150 Adolescents 175 200 Pregnant women Lactating women 150 Adults Recommended I 2 intake (μg/day) Age Group
    • 8. Effects of Iodine Deficiency Disorders Abortion Stillbirths Brain Damage - Cretinism Fetus Neonatal Goiter Brain Damage Neurobehavioral Neonate Goiter Thyroid Deficiency Impaired School Performance Retarded Physical Development Child Goiter with its Complications Thyroid Deficiency Impaired Mental Function Adult
    • 9. Pregnancy and Thyroid Function – The Mother <ul><li>Iodine clearance by the kidney increases - increased glomerular filtration </li></ul><ul><li>Iodine and iodothyronines transferred to fetus </li></ul><ul><li>Women living in low iodine intake areas may develop iodine deficiency and enlarged thyroid </li></ul><ul><li>The hypothalamic-pituitary-thyroid axis functions normally in pregnant women with adequate iodine </li></ul>
    • 10. Thyroid Adequacy Bad - - May not be good + - Good if treated early - + Good + + Outcome Fetal Maternal
    • 11. Pregnancy and Thyroid Function – Fetus / Neonate I <ul><li>Maternal hypothyroidism can be associated with neonatal defects (mental deficiency/ neurological defects/ low or normal IQs) </li></ul><ul><li>If infants have low T 3 and T 4 levels and elevated TSH levels, early appropriate treatment results in a normal intellect </li></ul>
    • 12. Pregnancy and Thyroid Function – Fetus / Neonate II <ul><li>NIS presence in mammary glands leads to secretion of iodine in milk, which is probably important for thyroid function in neonates </li></ul><ul><li>Prolactin stimulates NIS production which is inhibited by most anti-thyroidal agents, but not by perchlorate </li></ul>
    • 13. ClO 4 - in water - Detection <ul><li>1997 – Ion chromatography, assay sensitivity improved from 400ppb to 4 μg/L (4 ppb) </li></ul><ul><li>Public water supplies found to contain perchlorate ions: S California - 5-8 ppb; S Nevada - 5-24 ppb </li></ul><ul><li>Method modified for ClO 4 - detection in urine (LOD 500 ppb) and serum (LOD 50 ppb) </li></ul><ul><li>Electrospray ionization (ESI/MS/MS) (LOD 0.5 ppb) Less signal suppression by nitrate, bicarbonate and sulfate </li></ul>
    • 14. Perchlorate Potential Exposure Potential Risk <ul><li>Pathologic </li></ul><ul><li>Therapeutic </li></ul><ul><li>Pharmacology </li></ul><ul><li>Occupational </li></ul><ul><li>Environmental </li></ul><ul><ul><ul><li>Neonatal </li></ul></ul></ul><ul><ul><ul><li>Pediatric </li></ul></ul></ul><ul><ul><ul><li>Adult </li></ul></ul></ul><ul><ul><ul><li>Cancer </li></ul></ul></ul>
    • 15. Reported Deaths from Bone Marrow Toxicity among Perchlorate-treated Thyrotoxicosis Patients 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
    • 16. Therapeutic use of ClO 4 - 800-1000 mg/day then 1-6 months at lower doses Amiodarone induced (treatment for resistant tachyarryhthmias) 600-1000 mg/day Hyperthyroidism in pregnancy 600-900 mg/day Hyperthyroidism Dosage Indication
    • 17. Perchlorate Pharmacology I <ul><li>Pharmacology </li></ul><ul><ul><li>rapidly absorbed </li></ul></ul><ul><ul><li>excreted intact in the urine </li></ul></ul><ul><ul><li>half-life: 5-8 hr (humans) </li></ul></ul><ul><ul><li>95% recovered in urine over 72 hr </li></ul></ul><ul><ul><li>similar ionic size to iodide </li></ul></ul><ul><ul><li>competitive inhibitor of NIS </li></ul></ul>
    • 18. Perchlorate Pharmacology II <ul><li>May not be translocated into the thyroid cell </li></ul><ul><li>K i is estimated as 0.4-24 μM </li></ul><ul><li>May inhibit iodide accumulation -> goiter 1 and </li></ul><ul><li>lead to hypothyroidism if iodine intake low < 50-150 μg/day </li></ul><ul><li>May inhibit organic binding of iodine </li></ul><ul><li>by affecting thyroid peroxidase (not proven) </li></ul><ul><li>1 Toxic multinodular goiter (Plummer’s disease) refers to an enlarged multinodular </li></ul><ul><li>goiter commonly found in areas of iodine deficiency in which patients with </li></ul><ul><li>long-standing non-toxic goiter develop thyrotoxicosis </li></ul><ul><li>  </li></ul>
    • 19. Perchlorate Diagnostic Use <ul><li>The perchlorate discharge test - detect iodide organification defects (1000 mg) </li></ul><ul><li>Pertechnetate (Tc 99m) radiological studies to image brain, blood pool, localize the placenta. Pretreatment: 200-400 mg ClO 4 - minimizes pertechnetate in thyroid, salivary glands and choroid plexus </li></ul><ul><li>Perchlorate is used to block the gastric uptake of Tc 99m in the investigation of GI bleeding </li></ul>
    • 20. Perchlorate Epidemiological Studies Occupational Exposure <ul><li>To determine exposure levels and potential health effects need to estimate a safe working level of perchlorate </li></ul><ul><li>Much higher than environmental </li></ul><ul><li>Exposure: inhalation, ingestion , or dermal contact </li></ul><ul><li>Significant systemic absorption likely because of the high aqueous solubility at body temperature </li></ul><ul><li>USA: No occupational standard for perchlorate </li></ul><ul><li>OSHA regulates perchlorate as a nuisance dust (limit of 15 mg/m 3 (time-weighted average) </li></ul><ul><li>Safety concerns – it has explosive potential </li></ul>
    • 21. Occupational Studies <ul><li>Gibbs et al. (1998) Nevada </li></ul><ul><li>Cumulative exposure </li></ul><ul><ul><li>Average lifetime dose: 38 m g/kg </li></ul></ul><ul><ul><li>No adverse effects on thyroid </li></ul></ul><ul><li>Shift exposure </li></ul><ul><ul><li>Inhaled dose: 0.2-436  g/kg (ave 36  g/kg) </li></ul></ul><ul><li>Lamm et al. (1999) Utah </li></ul><ul><li>Cross sectional </li></ul><ul><li>Individual exposure </li></ul><ul><ul><li>Pre- post-shift urine </li></ul></ul><ul><li>Group exposure </li></ul><ul><ul><li>3 exposures & control group </li></ul></ul><ul><ul><li>Urine: 0.9 – 34 mg/shift (LOD=500 ppb) </li></ul></ul><ul><ul><li>Serum: 110 – 1600 ppb </li></ul></ul><ul><ul><li>(LOD 50 ppb) </li></ul></ul><ul><li>No adverse effects on thyroid function 0.01-34 mg/day </li></ul>
    • 22. Perchlorate Exposure <ul><li>Environmental </li></ul><ul><ul><ul><li>Neonatal </li></ul></ul></ul><ul><ul><ul><li>Pediatric </li></ul></ul></ul><ul><ul><ul><li>Adult </li></ul></ul></ul><ul><ul><ul><li>Cancer </li></ul></ul></ul><ul><li>Clinical Studies </li></ul>
    • 23. Neonatal Studies Environmental exposure <ul><li>1. CH data – no CH increase in exposed areas </li></ul><ul><li>2. T 4 - Las Vegas (+ ClO 4 - 15ppb) neonates compared with Reno(-) </li></ul><ul><li>No ClO 4 - effect </li></ul><ul><li>Brechner -Arizona </li></ul><ul><li>3. Neonatal TSH - Las Vegas (+ ClO 4 - ) neonates compared with Reno (-) </li></ul><ul><li>Perchlorate exposure had no effect </li></ul><ul><li>4.Chile – neonatal TSH (n=9,784). (100-120 ppb compared to low exposures 5-7 and <4ppb) </li></ul><ul><li>No differences found in TSH levels </li></ul><ul><li>Neonatal screening routine in most of the developed world </li></ul><ul><li>Congenital hypothyroidism (CH) treatable if caught early enough </li></ul>
    • 24. Pediatric Studies Environmental exposure <ul><li>Children and adolescents at greatest risk for low I 2 </li></ul><ul><li>Crump et al. studied school-age children (n = 162) </li></ul><ul><li>100-120 ppb, 5-7ppb and < 4ppb ClO 4 - in their drinking water </li></ul><ul><li>No differences found in TSH, FT 4 and goiter prevalence </li></ul>
    • 25. Adult Studies Environmental exposure <ul><li>Nevada Medicaid database (1997-1998) </li></ul><ul><li>Prevalence of thyroid diseases in areas exposed to ClO 4 - vs. areas unexposed </li></ul><ul><li>The prevalence rates of thyroid diseases was no greater in areas exposed to ClO 4 - in drinking water </li></ul>
    • 26. Thyroid Cancer Studies Environmental exposure <ul><li>Risk measures of thyroid cancer </li></ul><ul><ul><li>Prevalence, Mortality, Incidence </li></ul></ul><ul><li>All 3 measures showed no association with ClO 4 - exposure </li></ul><ul><li>ClO 4 - is non-mutagenic </li></ul>
    • 27. Prospective Volunteer Studies I <ul><li>900 mg/day ClO 4 - for 4 wks – FT 4 decreased; thyroid gland not depleted of iodine (Brabant et al. 1992) </li></ul><ul><li>I odine uptake inhibition studies (Lawrence et al. 2001) </li></ul><ul><ul><li>Thyroid function studies and iodine-uptake studies (prior/ during 2 wk exposure (3 mg or 10 mg ClO 4 - )/ 2 wks post-exposure </li></ul></ul><ul><ul><li>No effect on thyroid function studies (T 4 , T 3 , FTI, thyroid hormone binding ratio & TSH) </li></ul></ul><ul><ul><li>10 mg/day dosage </li></ul></ul><ul><ul><ul><li>38 % inhibition of iodine uptake </li></ul></ul></ul><ul><ul><ul><li>Serum ClO 4 - levels: 0.6 μg/ml (6 μM) </li></ul></ul></ul><ul><ul><li>3 mg/day dosage </li></ul></ul><ul><ul><ul><li>Serum ClO 4 - levels: below detection limit </li></ul></ul></ul><ul><li>A linear-log regression predicted a no-effect level of 2 mg/day </li></ul>
    • 28. Prospective Volunteer Studies II <ul><li>Greer et al. (2000) </li></ul><ul><li>35 mg/day, 7 mg/day, 1.4 mg/day and 0.5 mg/day </li></ul><ul><li>Found a significant inhibition of iodine uptake </li></ul><ul><li>A linear-log regression predicted a no-effect level of 0.5 mg/day </li></ul><ul><li>0.5 mg/day had no effect on iodine uptake </li></ul><ul><li>The data indicated a no-effect on iodine uptake level equivalent to an environmental ClO 4 - drinking water level of 250 μg/L </li></ul>
    • 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   Effect / endpoint   Daily Dose Body-Weight Adjusted Daily Dose i 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
    • 30. Model - Human Health and Perchlorate Exposure Ranges
    • 31. Summary I <ul><li>Thyroid - the critical effect organ of perchlorate toxicity </li></ul><ul><li>Perchlorate blocks iodide uptake by NIS </li></ul><ul><li>Assuming intake of 2 liters of water per day, the highest known level of ClO 4 - 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 </li></ul>
    • 32. Summary II <ul><li>Absence of an observed effect on neonatal thyroid, thyroidal diseases, or thyroidal cancer in areas with ClO 4 - in drinking water is epidemiologically consistent with human toxicological and pharmacological observations </li></ul>
    • 33. Summary III <ul><li>M ethods for measurement of ClO 4 - in urine, serum, solid matrix, and soil will need to be standardized in order to allow a better analysis and interpretation of data </li></ul>

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