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

Outline• Thyroid

• NIS

• Perchlorate

• Exposure ranges

• Occupational

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

Perchlorate (ClO4-) ion Characteristics

• A halogen Oxyanion:

Two fewer oxygen atomsClO-1 Hypochlorite

One less oxygen atomClO2-1 Chlorite

Most common formClO3 –1 Chlorate

One “extra” oxygen atom

Tetrahydron

ClOClO44-1-1 PerchloratePerchlorate

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

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

The Sodium-Iodide Symporter

Iodine

90 Fetus in uteri, Neonates and infants

90-120 Children

150 Adolescents

175

200

Pregnant women

Lactating women

150 Adults

Recommended

I2 intake (μg/day)

Age Group

Effects of Iodine Deficiency Disorders

AbortionStillbirthsBrain Damage - Cretinism

Fetus

Neonatal GoiterBrain Damage

Neurobehavioral

Neonate

GoiterThyroid DeficiencyImpaired School PerformanceRetarded Physical Development

Child

Goiter with its ComplicationsThyroid DeficiencyImpaired Mental Function

Adult

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

Bad--

May not be good+-

Good if treated early-+

Good++

OutcomeFetalMaternal

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 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

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 RiskPotential Risk

• PathologicPathologic

• TherapeuticTherapeutic• PharmacologyPharmacology

• OccupationalOccupational

• EnvironmentalEnvironmental• NeonatalNeonatal• PediatricPediatric

• AdultAdult• CancerCancer

StudyDaily

Dosage (mg/day)

Body Weight Adjusted Daily

Dosage (mg/kg/day)

Length ofTreatment for

each case

Effects

Hobson 1961 800800600

11119

14 weeks14 weeks20 weeks

Fatal aplastic anemia

Johnson & Moore 1961 10001000600

14149

3 months3 months1 month

Fatal aplastic anemia

Fawcett & Clark 1961 600600400

996

5 months5 months1-2 months

Fatal aplastic anemia

Krevans et al. 1962 800600600450

11996

2 weeks2 months2 months2 months

Fatal aplastic anemia

Gjemdal 1963 600600400

996

3 months3 months1 month

Fatal aplastic anemia

Barzilai and Sheinfeld 1966

10001000

1414

2 months2 months

Fatal aplastic anemia

10001000 1414 Few MonthsFew Months Fatal agranulocytosis

Reported Deaths from Bone Marrow Toxicity among Perchlorate-treated Thyrotoxicosis

Patients

Therapeutic use of ClO4-

800-1000 mg/day then 1-6 months at lower doses

Amiodarone induced

(treatment for resistant tachyarryhthmias)

600-1000 mg/dayHyperthyroidism in pregnancy

600-900 mg/dayHyperthyroidism

DosageIndication

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 andlead 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

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 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

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 µg/kg (ave 36 µg/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

Perchlorate Exposure

• Environmental• Neonatal• Pediatric

• Adult

• Cancer

• Clinical Studies

Neonatal Studies Environmental exposure

• 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 screening routine in most of the developed world•Congenital hypothyroidism (CH) treatable if caught early enough

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 < 4ppb ClO4- in their

drinking water

• No differences found in TSH, FT4 and goiter prevalence

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

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

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 exposediii 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)

600–1000mg400 mg agranulocytosis

8.5-14 mg/kg5.7 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 average2.5 mg34 mg

Per shift average0.036 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 μg20 μg

2.9μg/kg 0.29μg/kg

Model - Human Health and Perchlorate

Exposure Ranges

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