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Iodine and Perchlorate:

Further analysis of the


Chilean data set

March 21, 2008

John P Gibbs, MD
Medical Director,
Kerr-McGee
(retired)
A recent analysis of NHANES
2001-2002 data reported:
An association between altered thyroid function
(↑ TSH, ↓total T4) and increasing urine
perchlorate concentration among females age
12 and older.

The association with ↑TSH was found regardless


of urine iodide concentration

The association with ↓ total T4 was found only


among those females with urine Iodide
concentration < 100 /µg/L.
We accept that general iodine nutrition correlates with thyroid
function in the extremes of excess or deficiency BUT ….

Do we expect spot urine iodine levels to correlate with


any measures of thyroid function on an individual basis?

Do we even expect spot urine iodine levels at one point


in time to correlate with spot urine iodine levels in the
same individual at a different point in time?

Do we expect spot urine iodine levels at one point in time


to correlate with iodine nutritional status on an individual
basis? What about a 24 hour urine iodine measurement?
CHRONIC ENVIRONMENTAL EXPOSURE TO
PERCHLORATE IN DRINKING WATER AND THYROID
FUNCTION DURING PREGNANCY AND THE
NEONATAL PERIOD
Today I present a new analysis of the original Chilean study data with
emphasis on individual urine iodine and perchlorate concentrations. The
purpose is to evaluate whether or not the findings reported with the NHANES
dataset can be replicated with the Chilean dataset.
(funded by the PSG)

Rafael Téllez Téllez, Patricio Michaud Chacón, Carlos


Reyes Abarca, Cynthia B. Van Landingham, Kenny S.
Crump, John P. Gibbs
Naturally Occurring Perchlorate in Chile Characterized
Perchlorate Concentrations
(Drinking Water)
1999 2003
N ppb N ppb

Antofagasta 25 < 4.0 63 0.5

Chañaral 25 5.5 ± 1.6 54 5.8 ± 0.6

Taltal 25 112 ± 6.7 60 113 ± 13


Urinary Iodine Chile vs the U.S.
NHANES III, N=292 Chile, N=171 NHANES I, N=199
U r in a r y Io d id e , u g /L

800
715
700
9% of all samples < 100 µg/L
600
512
475
500
408
400 330 342
272
300 239
210
176
200 162
104 120 115
100 65

1 2 3 4 5
Quintile
NHANES: National Health And Nutritional Survey
Maternal Perchlorate Dose Estimates from Tellez et al

100%

90%

80%
Cumulative Percent

70%
Antofagasta
60%
Chanaral
50%
Taltal
40%
RfD

30%
NOEL

20%

10%

0%
0.00001 0.0001 0.001 0.01 0.1

Perchlorate Dose, mg/kg-day


Chile II: Pregnant Women Study Design
Conception Prenatal #1 Prenatal #2 Birth Postpartum

~16wks ~33wks ~38wks ~12wks

Serum Serum Cord serum Serum


Urine Urine Head Circumference Urine
Thyroid Exam Thyroid Weight Thyroid Exam
Exam
Water Length Breast Milk

Data Collected SERUM: T3, fT4, TSH, Tg, a-TPO, a-Tg


URINE: Iodine, creatinine
WATER: perchlorate
BIOLOGICAL MONITORING: serum, urine, milk samples
First Prenatal Visit
Antofagasta Chañaral Taltal

p-
N Mean N Mean N Mean val
ue*

Weeks gestation 46 16 46 17.1 64 15.3 0.05

T3 (ng/dL) 64 183 52 207 64 189 < .01

FreeT4 (ng/dL) 64 0.95 52 0.95 64 0.99 0.25

TSH ( μUl/ml) 64 2.63 52 2.81 64 2.61 0.91

Thyroglobulin
58 4.32 45 3.67 57 3.67 0.32
(ng/ml)

Iodine/g creatinine 61 391 38 355 57 322 0.06


*Kruskal Wallis
Second Prenatal Visit
Antofagasta Chañaral Taltal

N Mean N Mean N Mean p-value*

Weeks gestation 39 32.2 33 30.8 46 33.2 0.02

T3 (ng/dL) 48 196 40 206 38 173 0.003

FreeT4 (ng/dL) 48 0.86 40 0.82 38 0.83 0.015

TSH ( μUl/ml) 48 3.69 40 2.55 38 2.08 0.63

Thyroglobulin (ng/ml) 47 2.97 38 2.99 35 3.70 0.23

Iodine/g creatinine 47 368 27 422 37 358 0.08


*Kruskal Wallis
Neonatal (Cord Blood)
Antofagasta Chañaral Taltal

N Mean N Mean N Mean p-value*

T3 (ng/dL) 35 79 42 73 28 82 0.03

FreeT4 (ng/dL) 35 1.07 42 1.04 28 1.03 0.73

TSH ( μUl/ml) 33 6.20 40 6.69 28 6.31 0.99

Thyroglobulin
30 16.8 36 14.0 28 18.1 0.29
(ng/ml)

*Kruskal-Wallis
Maternal Free T4 vs Weeks Gestation
( Includes first and second prenatal visits )

2
Mixed Model Repeated Measures Regression of Free T4 w ith
Maternal Age and Weeks Gestation* , N=307, Variance =
Antofagasta Taltal Chanaral 0.01444

1.75 Free T4 = 1.919 - 0.399 x Maternal Age - 0.00800 x Weeks


Gestation

The dashed lines below are the 10th and 90th percentiles on
Reference Range
Non-Pregnant

1.5 the overall regression.

* Init ial regression using repeat ed measuresincluded a cit y ef f ect (p=0 1543) mat ernal age (p=0 004)
Free T4, ng/dL

1.25

0.75

0.5

0.25

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Weeks Gestation
We accept that general iodine nutrition correlates with thyroid
function in the extremes of excess or deficiency BUT ….

Do we expect spot urine iodine levels to correlate


with any measures of thyroid function on an
individual basis?

Do we expect spot urine iodine levels at one point in time to


correlate with spot urine iodine levels in the same individual at a
different point in time?

Do we expect spot urine iodine levels at one point in time to


correlate with iodine nutritional status on an individual basis? What
about 24 hour urine iodine measurements?
Chile II: Pregnant Women Study Design
Conception Prenatal #1 Prenatal #2 Birth Postpartum

~16wks ~33wks ~38wks ~12wks


TSH N=152 TSH N=68 TSH N=31
fT4 N=148 fT4 N=54 fT4 N=13

220 Measurements on 155


Serum
Individuals for TSH,Serum
202 Cord serum Serum
Urine
Measurements Urine
on 149 Head Circumference Urine
individuals
Thyroid Examfor free T4
Thyroid Weight Thyroid Exam
Exam
Water
(who also had urine iodide, Length Breast Milk
urinary perchlorate, and urine
creatinine measurements)
SERUM: T3, fT4, TSH, Tg, a-TPO, a-Tg
URINE: Iodine, creatinine
Data Collected
WATER: perchlorate
BIOLOGICAL MONITORING: serum, urine, milk samples
Regression Analysis
AgeX
Weeks gestation Free T4, not TSH
Smoking X
Urine Perchlorate & ratio X
Urine iodine &ratio Free T4 & TSH (ratio only)
Perchlorate – Iodine interaction X
Controlled for repeat analyses on same
individuals X
Regression Results
Urine
Dependent Independent I- and Urine ClO4- concentration metrics
Variable Parameter
µ/L µ/g creat

β-coefficient p-value β-coefficient p-value

free T4 Weeks gestation -.000503 <.0001 -.000481 <.0001


Urine I- -.000137 0.009 -.0000160 0.011

Urine ClO4- - - - -
Coefficients
I- - ClO4-are such that -both TSH- & free T4
Interaction - -
decrease with increasing spot urine iodine levels
Ln(TSH) Weeks gestation - - - -
Urine I- - - .0000730 0.0254

Urine ClO4- - - - -
I- - ClO4- Interaction - - - -
Urinary Iodine: µ/L vs µ/g-creat
For the most part, the graphics that I am
going to show appear very similar for both
measures
All graphics of based on the study of
pregnant women in Chile are based on
urine iodide (µ/L)
Spot Urine Iodine Cumulative Distribution
First Prenatal Second Prenatal

100%
C u m u la tiv e P e rc e n ta g e

90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 100 200 300 400 500 600 700 800 900 1000

Spot Urine Iodine, mcg/L


17 measurements
on 16 individuals

0 100 200 300 4


Analysis of Individuals < 100 µ/L
Free T4 is not lower and ln(TSH) is not higher
than individuals with iodine ≥100 µ/L

Urine ClO4- did not correlate with free T4 or


ln(TSH), whether or not concentrations were
creatinine adjusted and whether or not urine I- or
weeks gestation were included in the analysis

N was small
Free T4 (gestation corrected) vs Urine Iodine Categorized by Urine Perchlorate

<10 10-19 20-49 50-99 ≥100

2.0
1.8
1.6
1.4
1.2
fre e T 4

1.0
0.8
0.6
0.4
0.2
0.0
0 100 200 300 400 500 600 700 800 900 1000
Urine Iodine, mcg/L
Free T4 (gestation corrected) vs Urine Iodine Categorized by Urine Perchlorate

≥100

2.0
1.8 Free T4 does not decrease with
1.6 decreasing iodine for those women
with urine perchlorate ≥100 µ/L
1.4
1.2
fre e T 4

1.0
0.8
0.6
0.4
0.2
0.0
0 100 200 300 400 500 600 700 800 900 1000
Urine Iodine, mcg/L
TSH vs Urine Iodine Categorized by Urine Perchlorate
<10 10-19 20-49 50-99 ≥100

10

1
T S H

0.1
0 100 200 300 400 500 600 700 800 900 1000
Urine Iodine, mcg/L
TSH vs Urine Iodine Categorized by Urine Perchlorate
≥100

10

1
T S H

TSH does not increase with


decreasing iodine for those women
with urine perchlorate ≥100 µ/L

0.1
0 100 200 300 400 500 600 700 800 900 1000
Urine Iodine, mcg/L
Free T4, Controlled for age & gestation, Categorized by Urine
Iodine
<100 100-199 200-399 >400 mean T4

2.0
1.8
1.6
1.4
1.2
fre e T 4

1.0
0.8
0.6
0.4
0.2
0.0
0 100 200 300 400 500 600 700 800 900 1000
Urine Perchlorate, mcg/L
Free T4, Controlled for age & gestation, Categorized by Urine
Iodine
<100 100-199 200-399 >400 mean T4

2.0
1.8
1.6 Free T4 does not decrease with
1.4 increasing perchlorate for those
1.2 women with urine iodine < 100 µ/L
fre e T 4

1.0
0.8
0.6
0.4
0.2
0.0
0 100 200 300 400 500 600 700 800 900 1000
Urine Perchlorate, mcg/L
TSH Categorized by Urine Iodine
<100 100-199 200-399 >400 log mean TSH

10

1
T S H

0.1
0 100 200 300 400 500 600 700 800 900 1000
Urine Perchlorate, mcg/L
TSH Categorized by Urine Iodine
<100 100-199 200-399 >400 log mean TSH

10

1
T S H

TSH does not increase with increasing


perchlorate for those women with
urine iodine < 100 µ/L

0.1
0 100 200 300 400 500 600 700 800 900 1000
Urine Perchlorate, mcg/L
We accept that general iodine nutrition correlates with thyroid
function in the extremes of excess or deficiency BUT ….

Do we expect spot urine iodine levels to correlate with


any measures of thyroid function on an individual basis?

Do we expect spot urine iodine levels at one point in


time to correlate with spot urine iodine levels in the
same individual at a different point in time?

Do we expect spot urine iodine levels at one point in time


to correlate with iodine nutritional status on an individual
basis? What about 24 hour urine iodine measurements?
Chile study: Tellez et al 2005

One of very few studies that evaluated


urine iodine on the same individuals at two
or more points in time

Most reported studies cross sectional at a


single point in time
Chile II: Pregnant Women Study Design
Conception Prenatal #1 Prenatal #2 Birth Postpartum

~16wks ~33wks ~38wks ~12wks

Serum Serum Cord serum Serum


Urine Urine Head Circumference Urine
Thyroid Exam Thyroid Weight Thyroid Exam
Exam
Water Length Breast Milk

Data Collected SERUM: T3, fT4, TSH, Tg, a-TPO, a-Tg


URINE: Iodine, creatinine
WATER: perchlorate
BIOLOGICAL MONITORING: serum, urine, milk samples
Spot Urine Iodine Cumulative Distribution
First Prenatal Second Prenatal Post Partum

100%
C u m u la tiv e P e rc e n ta g e

90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 100 200 300 400 500 600 700 800 900 1000

Spot Urine Iodine, mcg/L


First Prenatal Iodine Distribution

700
* 134 subjects had a spot urine iodine determination at their first
prenatal visit 578

600

500
Median Urine Iodine, ug/L

343
400
279

300
204

200 128

100

0
1 2 3 4 5
Quintile
Comparison of First Prenatal Iodine Distribution with
Subsequent Urine Iodine Distribution

First Prenatal Subsequent Test*

700
* 134 subjects had a spot urine iodine determination at their first
prenatal visit and at least one more spot urine iodine
600 determination at the second prenatal visit or post partum visit. If 578
two additional tests were obtained, the average of the two was
used

500
Median Urine Iodine, ug/L

400
343

300 279 273


257
237 243 243

204
200
128

100

0
1 2
Quintile 3 Prenatal 4
at First 5
Visit
First Prenatal Maternal Iodine compared with Second Prenatal and Postpartum
Iodines

Second Prenatal Postpartum

1000
Io d in e ,

900
R2 < 0.0001
800
S e c o n d P re n a ta l o r P o s tp a rtu d m

700

600
u g /L

500

400

300

200

100

0
0 200 400 600 800 1000 1200

First Prenatal Iodine, ug/L


We accept that general iodine nutrition correlates with thyroid
function in the extremes of excess or deficiency BUT ….

Do we expect spot urine iodine levels to correlate with any


measures of thyroid function on an individual basis?

Do we expect spot urine iodine levels at one point in time to


correlate with spot urine iodine levels in the same individual at a
different point in time?

Do we expect spot urine iodine levels at one point in time to


correlate with iodine nutritional status on an individual basis?
What about 24 hour urine iodine measurements?
Haddow JE, McClain MR, Palomaki GE, Hollowell JG. Urine iodine
measurements, creatinine adjustment, and thyroid deficiency in an adult United
States population. J Clin Endocrinol Metab. 2007 Mar;92(3):1019-22. Epub 2007
Jan 2.

“Using the Health and Nutrition Surveys III data set, we


examined median TSH and total T(4) values according
to deciles of urine iodine (with and without creatinine
correction). Stepwise regression analysis was used to
further explore these relationships in the context of
possible confounding variables…

“A multivariate regression analysis that accounts for age,


body mass index, race, creatinine, iodine, estrogen use,
smoking, and gender reveals only a weak association
between levels of urine iodine and markers of thyroid
function.”

“Our analyses indicate that the U.S. nonpregnant adult


population is iodine sufficient
Regarding Spot Urine Iodine Levels

World Health Organization (WHO) recommends


interpreting urine iodine levels on a population basis, not
an individual basis: “the median UI concentration in
iodine-sufficient populations should be greater than 100
mcg/L, and no more than 20% of the population should
have UI concentrations below 50 mcg/L”

NAS 2005 “the distribution of iodide values measured in


spot urine samples is broader than values measured
repeatedly in individual subjects (Andersen et al. 2001);
this leads to overestimation of the number of subjects
with both low and high values.”
Andersen S, Pedersen KM, Pedersen IB, Laurberg P 2001 Variations in
urinary iodine excretion and thyroid function. A 1-year study in healthy men.
Eur J Endocrinol 144:461–465

“The iodine intake level in a population is determined in cross-


sectional studies. A fraction of samples with iodine content
below a certain level, e.g. 25 mcg/l, may suggest iodine
deficiency in part of the population.”

“…urinary iodine varies considerably from day to day and the


fraction of low samples caused by dispersion remains
unsettled.”

“A longitudinal study of 16 healthy men living in an area of


mild to moderate iodine deficiency. …measured urinary iodine
…concentrations) in samples collected monthly for 1 year.”

“Average urinary iodine excretion was 57.0 microg/l and


varied from 29 to 81 microg/l. Individual samples varied
between 10 and 260 microg/l, and the variation around the
mean was 2.4 times larger when calculated for the 180
individual samples compared with the 15 average annual
values….”
Andersen S, Karmisholt J, Pedersen KM, Laurberg P.Reliability of
studies of iodine intake and recommendations for number of samples
in groups and in individuals. Br J Nutr. 2008 Apr;99(4):813-8. Epub
2007 Oct 26.

“…estimating population iodine excretion


requires 100-500 spot urine samples for
each group or subgroup.”

“Less than ten urine samples in an


individual may be misleading.”
24 Hr urine Iodine: the “gold
standard”
Considered better than spot urine iodine
Considered better than creatinine adjusted
spot urine iodine
Still evaluates only the previous ~ 24 hour
iodine intake (t½ ~ 6hrs)
Individual iodine nutritional status likely
depends upon average iodine intake over
the previous days, weeks or months
Thank You

This presentation and


data analysis funded by
the Perchlorate Study
Group and prepared in
a tranquil setting
Source: Drawn from the original NHANES data by the Bio-Statistical Center of the Catholic University of Leuven,
Courtesy of Dr. Gail Charnley
Source: Drawn from the original NHANES data by the Bio-Statistical Center of the Catholic University of Leuven,
Courtesy of Dr. Gail Charnley

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