2002 CPEO Military List Archive

From: Lenny Siegel <lsiegel@cpeo.org>
Date: 3 Jul 2002 04:56:00 -0000
Reply: cpeo-military
Subject: [CPEO-MEF] Perchlorate
The following analysis of the impact of perchlorate exposure, from Tom
Zoeller <tzoeller@bio.umass.edu> is designed to clarifly an earlier posting.


First, the description and interpretation of the negative feedback
system of thyroid hormone regulation is often misinterpreted in some of
its details as it relates to thyroid toxicology. Specifically, the
negative feedback system of the HPT axis limits the degree to which
circulating levels of thyroid hormone can change within a specific
range. However, it is not accurate to assume that the negative feedback
system prevents adverse effects of small changes in circulating levels
of thyroid hormone. The general logic applied to this system is as
follows: When circulating T4 declines, the secretion of TSH from the
pituitary gland increases. Increased circulating TSH will have the
effect of stimulating the thyroid gland to increase synthesis and
secretion of T4 and T3. This system maintains circulating levels of T4
within narrow individual limits under normal conditions (Andersen et
al., 2002). However, it is not logical to extend this observation to
conclude that this negative feedback system prevents T4 levels from
declining under conditions of perchlorate exposure. Rather, it is
important to recognize that circulating TSH will increase only when the
hypothalamic-pituitary system detects a reduction, slight as it may be,
in circulating levels of thyroid hormone. Therefore, if TSH levels are
increased, despite measuring "normal" levels of T4, it demonstrate that
T4 levels are in fact reduced. An important question is whether subtle
reductions in circulating T4 that trigger an increase in TSH release is
detected as thyroid hormone insufficiency in other tissues including the
fetal brain. Therefore, the implicit assumption often made is that the
HPT axis is more sensitive to small changes in circulating levels of
thyroid hormone than any other tissue. There is no formal evidence to
support this hypothesis. 

Two recent human studies support the interpretation that modest changes
in circulating levels of T4 can produce adverse effects in adults.
First, Andersen et al. (Andersenet al., 2002) demonstrated in humans
that individual variation in T4 levels are much more narrow than the
population variance in T4 which is the basis for the normal reference
range. Second, long-term follow-up studies of patients given T4
replacement therapy following thyroid ablation for thyroid cancer or
Grave's disease (Osman et al., 2002). These patients exhibit a much
higher incidence of cardiovascular disease. The interpretation is that
chronic, sustained elevations in circulating levels of T4 can produce
adverse effects on the cardiovascular system. 


The second issue relates to the logic used to interpret perchlorate
effects on circulating levels of thyroid hormone in the Greer study . It
is logical to conclude that, within a short period, the critical event
upon which predicted health effects of perchlorate in adults should be
based is a change in circulating levels of thyroid hormones. The logic
is that, if perchlorate affects only the thyroid gland (and there is a
great deal of evidence to support this view), adverse consequences of
perchlorate exposure can only be presumed when the dose is high enough
to cause a reduction in circulating levels of thyroid hormone. However,
the human adult thyroid gland contains perhaps several months worth of
T4 stored in the colloid. Therefore, it appears arbitrary to choose the
0.5 mg/kg/day dose level (the highes dose used by Greer et al.) for the
NOAEL. Clearly, if the Greer study had used 1.0 mg/kg/day, this would
have been the NOAEL (or 5 mg/kg/day). In fact, the question is whether
there is a dose of perchlorate that would affect circulating levels of
thyroid hormone in normal, euthyroid individuals within a 14 day period. 

Considering this, it is important to question the applicability of the
Greer study to pregnant and lactating women, and their offspring, within
even a short time period. Perchlorate may be transported by the
sodium-iodide symporter (NIS) instead of iodide. Therefore, because the
NIS is induced in lactating breast tissue by prolactin (Perron et al.,
2001; Rillema and Rowady, 1997; Rillema et al., 2000; Spitzweg et al.,
1998), it is possible that perchlorate is concentrated in milk (Howard
et al., 1996; Mountford et al., 1986). (note: in experimental animals,
it has been suggested that perchlorate levels in milk are about 2-times
that of maternal serum). In addition, it is clear that perchlorate will
reduce iodide uptake into milk, thus reducing the sole source of iodine
to the infant. A 14 day exposure of a lactating woman to 35 grams of
perchlorate per day (this is the dose that the Greer study used that had
no effect on adult thyroid hormone levels) may expose the infant to
considerably more perchlorate than 200 µg/kg/day. There are two reasons
this should be considered carefully. First, the dose response
relationship between serum perchlorate and RAIU inhibition in infants is
unknown. However, we can assume it is similar to that in adults since
the NIS protein itself is not different. The fetal thyroid gland does
not begin to function until the second trimester, but for the 2nd and
3rd trimesters, the fetus may be damaged by RAIU inhibition even if the
mother is not so affected. For example, Haddow et al. (Haddow et al.,
1999) showed that maternal hypothyroxinemia (not hypothyroidism) was
associated with measurable neurological deficits in their offspring,
despite the fact that their children were euthyroid. Moreover, the
duration of NIS inhibition required to produce significant decrements in
circulating levels of T4 is unknown for the fetus and neonate. However,
it is known that a 14 day period of thyroid hormone insufficiency is
long enough to produce measurable neurological deficits in newborns (van
Vliet, 1999). Moreover, Vulsma et al. (Vulsma et al., 1989) estimated
that the neonatal thyroid gland contains thyroid hormones equivalent to
only a single day secretion. This estimate was revised by van den Hove
et al. (van den Hove et al., 1999) who empirically measured
intrathyroidal stores of thyroid hormones in human fetuses and neonates
and found that the amount of hormone stored in the colloid is less than
that required for a single day. Thus, fetuses, neonates and infants
represent a sizable population at risk of permanent damage caused by
thyroid hormone insufficiency. In addition, they exhibit known
differences in iodine requirements and fluid consumption compared to
adults, and the duration they can withstand reduced thyroid hormone
synthesis before sustaining a decreased circulating level of thyroid
hormone is considerably less than that of a normal adult. 

Thus, while the Greer et al. study is a perfectly good study, it is
important to look carefully at several of these aspects. For example, as
Greer himself points out, if perchlorate does not inhibit thyroid iodide
uptake, it cannot impact the thyroid system. This is true for the adult
as well as for the fetus/neonate/infant. Moreover, because perchlorate
clears rapidly from the system, incidental exposure to perchlorate would
not be expected to produce significant effects on iodide uptake.
However, it is a mistake to conclude based on the Greer study (that 0.5
mg/kg/day of perchlorate for 14 days did not affect thyroid hormone
levels in healthy adults) that this level of perchlorate will not affect
the human thyroid gland. Rather, it is more logical to conclude that
levels of perchlorate that do not affect iodide uptake in the thyroid
gland of healthy adults will likely not affect iodide uptake in the
fetus/neonate/infant. Then the only question is: what is the level of
exposure of perchlorate to the fetus/neonate/infant. 


If the adverse effects of perchlorate are mediated by its action on
thyroidal iodide uptake leading to reduced circulating levels of thyroid
hormone, then thyroid hormone-responsive endpoints should be evaluated
in experimental studies. The problem is that there are few if any
well-characterized neurodevelopmental endpoints that have been evaluated
in a perchlorate study. Therefore, an important source of information is
missing (the effects of perchlorate and very slight changes in maternal
thyroid hormone on brain development). Minimally, the relationship
between perchlorate, thyroid hormone, and thyroid hormone responsive
endpoints needs to be better developed in the literature. 


Andersen S, Pedersen KM, Bruun NH, Laurberg P (2002) Narrow individual
variations in serum T(4) and T(3) in normal subjects: a clue to the
understanding of subclinical thyroid disease. J Clin Endocrinol Metab

Howard BJ, Voigt G, Segal MG, Ward GM (1996) A review of countermeasures
to reduce radioiodine in milk of dairy animals. Health Physics

Ladenson PW (2000) Diagnosis of hypothyroidism. In: Braverman LE, Utiger
RD, ed, Werner and Ingbar's The Thyroid: A fundamental and Clinical
Text. Lippincott Williams and Wilkins, Philadelphia, 848-852. 

Mountford PJ, Coakley AJ, Fleet IR, Hamon M, Heap RB (1986) Transfer of
radioiodide to milk and its inhibition. Nature 322:600 

Osman F, Gammage MD, Sheppard MC, Franklyn JA (2002) Clinical review
142: cardiac dysrhythmias and thyroid dysfunction: the hidden menace? J
Clin Endocrinol Metab 87:963-967. 

Perron B, Rodriguez AM, Leblanc G, Pourcher T (2001) Cloning of the
mouse sodium iodide symporter and its expression in the mammary gland
and other tissues. J Endocrinol 170:185-196. 

Rillema JA, Rowady DL (1997) Characteristics of the prolactin
stimulation of iodide uptake into mouse mammary gland explants. Proc Soc
Exp Biol Med 215:366-369 

Rillema JA, Yu TX, Jhiang SM (2000) Effect of prolactin on sodium iodide
symporter expression in mouse mammary gland explants. Am J Physiol
Endocrinol Metab 279:E769-772. 

Spitzweg C, Joba W, Eisenmenger W, Heufelder AE (1998) Analysis of human
sodium iodide symporter gene expression in extrathyroidal tissues and
cloning of its complementary deoxyribonucleic acids from salivary gland,
mammary gland, and gastric mucosa. J Clin Endocrinol Metab 83:1746-1751 

van den Hove MF, Beckers C, Devlieger H, de Zegher F, De Nayer P (1999)
Hormone synthesis and storage in the thyroid of human preterm and term
newborns: effect of thyroxine treatment. Biochimie 81:563-570. 

van Vliet G (1999) Neonatal hypothyroidism: Treatment and Outcome.
Thyroid 9:79-84 

Vulsma T, Gons MH, deVijlder J (1989) Maternal-fetal transfer of
thyroxine in congenital hypothyroidism due to a total organification
defect of thyroid agenesis. N Engl J Med 321:13-16 

R. Thomas Zoeller  
Biology Department  Morrill Science Center  
University of Massachusetts  Amherst, MA 01003  
Phone: 413-545-2088  
Fax: 413-545-3243  
email: tzoeller@bio.umass.edu  
Zoeller Lab Website: http://www.bio.umass.edu/biology/zoeller/  
Graduate Program: http://www.bio.umass.edu/mcb/index.html 



Lenny Siegel
Director, Center for Public Environmental Oversight
c/o PSC, 278-A Hope St., Mountain View, CA 94041
Voice: 650/961-8918 or 650/969-1545
Fax: 650/961-8918

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