Thyroid hormone metabolism and environmental chemical exposure
Leijs et al. Environmental Health
Thyroid hormone metabolism and environmental chemical exposure
Marike M Leijs 0 1 3
Gavin W ten Tusscher 7
Kees Olie 6
Tom van Teunenbroek 5
Wim MC van Aalderen 3
Pim de Voogt 1 6
Tom Vulsma 3
Alena Bartonova 4
Martin Krayer von Krauss 9
Claudia Mosoiu 8
Horacio Riojas-Rodriguez 2
Gemma Calamandrei 10
Janna G Koppe 11
0 University Hospital Aachen RWTH, Department of Dermatology , Pauwelstrasse 30, 52074 Aachen , Germany
1 IBED/ESS, University of Amsterdam , Amsterdam , The Netherlands
2 National Institute of Public Health , Cernavaca, Morelos , Mexico
3 Department of Paediatrics and Neonatology, Emma Children's Hospital Academic Medical Centre , Amsterdam , The Netherlands
4 NILU - Norwegian Institute for Air Research , Kjeller , Norway
5 Ministry of Housing, Spatial Planning and the Environment , The Hague , The Netherlands
6 KWR Watercycle Research , POBox 1072, 3430 BB Nieuwegein , The Netherlands
7 Department of Paediatrics and Neonatology , Westfriesgasthuis, Maelsonstraat 3, 1624 NP Hoorn , The Netherlands
8 Institute of Food Bioresources (IBA) , Bucharest , Romania
9 WHO, Regional Office for Europe , Copenhgen, Scherfigsvej 8 , Denmark
10 Istituto Superiore di Sanita , Rome , Italy
11 Ecobaby Foundation , Hollandstraat 6, 3634 AT Loenersloot , The Netherlands
Background: Polychlorinated dioxins and -furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism. Influences of brominated flame retardants, PCDD/F's and dioxin like-PCBs (dl-PCB's) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3', 5,5'tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3',5triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort. Methods: Vena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels. Results: The current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group. Conclusion: Once again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.
From HENVINET (Health and Environment Network) final conference
Brussels, Belgium. 14 April 2010 - 15 April 2010
Polychlorinated biphenyls (PCBs) and dioxins (PCDDs/Fs),
especially TCDD (2,3,7,8-tetrachloro-dibenzo-p-dioxin)
are well known developmental endocrine disruptors.
PCDDs/Fs and planar (dioxin-like, dl-) PCBs are often
grouped together as dioxins or dioxin-like compounds,
because of their common mode of (toxic) action, via the
PCDDs and PCDFs are unwanted by-products of the
production of chlorinated phenols, metallurgic processes,
bleaching of paper pulp and the incineration of waste
[1-3]. PCBs have been produced world-wide from the
1930s and were mainly used as dielectric fluids in
electrical transformers and capacitors, as heat exchange or
hydraulic fluids .
The polybrominated diphenylethers (PBDEs) have
been widely used over the last few decades as flame
retardants in various materials such as electronic
equipment, plastics, foams (e.g. used in car seats and
furniture), carpet liners and textiles. Humans are exposed to
PBDEs mainly by ingestion (from food and milk) and by
inhalation of indoor air and dust. Currently, these
compounds are frequently detected in humans all over the
world [5,6]. The penta- and octa brominated
diphenylethers are banned in the European Union, but are still
present in the environment. Furthermore, three others,
also blamed for interfering with thyroid hormone
metabolism are still in use, decabromo diphenyl ether
(DBDE), hexabromocyclododecane (HBCD), and
tetrabromobisphenol A (TBBPA). The first two were
extensively addressed in the HENVINET project. This FP6
EU HENVINET project aimed at synthesizing scientific
information available on a number of topics of high
relevance to researchers and policy makers in the field
of environment and health (E.C. grant: HENVINET
037019). The third one TBBPA is currently found in
human beings and can traverse the placenta as it has
been found in babies born by caesarean section in
hospitals.  TBBPA has a half life of 2 days and is
excreted as a glucuronide or a sulphate in the faeces via
the bile. In animal studies effects are detected on the
apical part of the cochlea and an increase in pituitary
weight was observed [8,9]. The specific thyroid hormone
nuclear receptor TR- 2, only present in the cochlea,
pituitary gland and hypothalamus might play a role.
Considering the findings in babies born in hospital the
margin of exposure is very low and current use of
TBBPA is therefore a matter of concern for human
health, especially in the perinatal period. Thyroid
hormone is essential for normal body metabolism, growth,
and development including reproduction, maturation
and ageing. Fluctuations in thyroid hormone levels are
able to alter outcomes in children [10,11].
Large amounts of these compounds have been released
into the environment through the processes previously
stated. Organisms, and ultimately humans, are exposed via
ingestion (food, drinking water), via inhalation, and via
dermal contact. Ingestion is the main source (90%) of
exposure, primarily through meat and meat products
(2327%), dairy products (17-27%) and fish (16-26%) . Due
to the accumulating properties of these compounds, each
step higher in the food chain increases the concentration
of dioxins in an organism (bioaccumulation). Once
ingested, dioxins and PCBs are primarily stored in the
liver followed by the adipose tissue. After ingestion dioxins
and PCBs are detectable for a long period. The mean
halflife of dioxins and PCBs in the human body is assumed to
be 7 to 9 years .
Dioxins, PCBs and PBDEs are also able to cross the
placenta . In addition, they are excreted in breast milk
and thereby cause significant exposure to nursing offspring
. Adolescents, undergoing hormonal changes during
puberty, are probably also at greater risk of susceptibility,
and therefore at higher risk, with regards to environmental
exposure health effects .
Background concentrations, concentrations that
average individuals in Europe and the US are daily exposed
to, have been related to various negative health effects.
Studies have shown negative effects on lung function
[17,18], and haematological and immunological
disturbances [19-21]. In addition, an increase in behavioural
problems was seen, and prolonged evoked responses
measured with EEG (electro-encephalography) and MEG
(magneto-encephalography), and possible indications of
subtle neurological abnormalities were found in children
Previous studies of the current cohort showed a higher
T4/TBG ratio that became significantly higher at 7 days
and 11 weeks after birth, together with an increase in
TSH. This finding was interpreted as an hypothyroidal
state of the hypothalamic cells involved in thyroid
hormone metabolism caused by dioxins .
In this study thyroid hormone parameters were
investigated in relation to prenatal and early postnatal PCDD/F
exposure and current exposure of PCDD/F and dl-PCBs
and the lower brominated PBDEs during adolescence.
This study is part of a longitudinal cohort study of 14-19
year old children, studied during their neonatal (n=60),
 toddler (n=60)  and pre-pubertal period (n=41)
. All 33 children (18 girls and 15 boys) participating
in the current follow-up were born in the Amsterdam/
Zaandam region. Twenty-five of the children are still
inhabitants of the region. PCDD/F exposure was determined in
the perinatal period in breast milk. Of the total cohort of
41 subjects who participated in the pre-pubertal study, one
subject was excluded from the current follow-up because
of a Ewing sarcoma and one was partly excluded because
of an extra Y-chromosome (XYY). Five subjects declined
to participate in the new follow-up, three could not be
traced. One of the children, who did not participate in the
pre-pubertal follow-up, consented to the current follow
up. Of the 33 examined adolescents 2 refused to undergo
vena puncture and 2 refused a repeated puncture after
blood clotting in the first needle.
The study was approved by the institutional medical
ethics committee. All participants of the study and their
parents signed an informed consent.
Perinatal PCDD/F levels and current serum levels of
PCDD/Fs, dl-PCBs and PBDEs were measured in an
uncontaminated laboratory dedicated to low-level dioxin
sample treatment, at the Environmental Chemistry Section
of IBED/ESS of the University of Amsterdam.
Concentrations of the 19 most toxic PCDD/F congeners (seven
PCDDs and twelve PCDFs) and the concentration of 3
dlPCBs (77, 126, 169) and 8 PBDEs (28, 47, 85, 99, 100, 153,
154 and 183) were determined. The concentration of
PCDD/F and dl-PCB congeners are expressed in toxic
equivalents (TEQ) ng/kg=pg/g fat.
An activated carbon column (Carbosphere) was used
for group separation of the chemicals. The PCDD/F and
dl-PCB fraction was isolated and a clean-up was
performed using a column of AgNO3 on silica gel and a
column of activated Al2O3 on silica gel. The PBDE fraction
was purified using activated Al2O3 on silica gel and an
activated alumina column. After concentrating the
sample, quantification of dioxins and dl-PCBs was done
using hr-GC/hr-MS. PBDEs were determined by hr-GC/
lr-MS. As an internal standard, a mixture of 13C-labelled
PCDD/Fs, dl-PCBs and PBDEs was used. More detailed
information about the analysis have been published
PCDD/F concentrations were previously determined in
the mothers milk 3-4 weeks after birth, which is indicative
of the prenatal exposure. The cumulative total postnatal/
lactational exposure was calculated as the measured
Table 1 Dioxin, dl-PCB and PBDE exposure
Current serum dl-PCBs WHO-TEQ (pg/g lipid)
Current serum PBDE (ng/g lipid) n=17*
PCDD/F concentration in breast milk multiplied by the
total breast milk intake.  Results see table 1.
For statistical analyses the non-parametric Spearmans
correlation coefficient was calculated using SPSS- 14.0.
The level of significance was 5% (P=0.05) for the analysis
with the predicted variables. For the congener specific
analysis the level of significance was 5/8% (P=0.0063), to
correct for the number of analyses.
As outcome variables we used serum T3, T4, FT4,
TSH and TBG. The prenatal, lactational and current
serum PCDD/Fs and the current serum dl-PCBs and
PBDE levels were the predicted variables using the
Spearmans correlation coefficient. A congener specific
analysis of the PBDEs was performed.
95% confidence interval
Means, ranges, standard deviation and 95% confidence interval of the exposure to Dioxins, PCBs and PBDEs.
*Current serum PBDE levels is calculated with exclusion of the outlier (73.6 ng/g lipids)
Table 2 Thyroid hormone metabolism parameters
Measured objective n=29
Free thyroxin (FT4) pmol/L
Triiodothyronin (T3) nmol/L
Thyroxin-binding globulin (TBG) mg/L
Thyroid stimulating hormone (TSH) mU/L
95% confidence interval
Thyroid hormone metabolism parameters, means, ranges, standard deviation and 95% confidence interval.
Reference intervals: FT4: 9-22 rmol/L, T4: 70-140nmol/L, T3: 1.2-3.0 nmol/L, TBG: 7-17 mg/L, TSH: 0.5-5.7 mU/L.
In an earlier study of our cohort an increase in T4
and T4/TBG ratio was seen in children with higher
dioxin levels in their breastmilk in the first and eleventh
week postpartum . The children now in their
adolescence have normal serum TSH and T4 values.
TSH levels were significantly increased in relation to
prenatal exposure at eleven weeks postpartum. None of
these TSH-levels were above the WHO cut-off point of
5 mU/L, now also proposed to use as a biomarker for
dioxin toxicity. However we have found effects on brain
development in our cohort at the age of 8-12 years of
age, while no baby had a TSH above 5 mU/L in their
postnatal period  . Based on these outcomes it
would seem a major error for governmental bodies to
use a cut-off point of 5 mU/L as a biomarker for dioxin
T3 is a product of the target organs. It looks as if the
damage done by the two pollutants dl-PCBs and BDE 99
Figure 1 Serum dl-PCBs and T3 levels (P=0.047) in the individuals at the age of 14-18 years Serum dl-PCBs and T3 levels (P=0.047) in the
individuals at the age of 14-18 years
Figure 2 Serum BDE-99 levels and T3 (P=0.003) in the individuals of the cohort at the age of 14-18 years. Serum BDE-99 levels and T3
(P=0.003) in the individuals of the cohort at the age of 14-18 years.
resulting in higher T3 levels takes place in the peripheral
target organs perhaps by negatively influencing transporter
proteins. It is widely known and accepted that human
beings have effective compensation mechanisms. For
instance the brain is capable of keeping T3 levels constant
over a wide range (30-200 % of normal) of T4 levels by
adapting the different deiodinases. However it is possible
that with environmental pollutants transporter proteins
are negatively influenced like for example the
monocarboxylate transporter 8 (MCT 8), a protein necessary for
the transport of T4 and T3 over the membrane into the
cell in the hypothalamus, and when this transporter
protein is lower or absent severe mental problems can arise as
is seen in the Allan-Herndon-Dudley syndrome, a genetic
MCT 8 deficiency, that is characterized by severe mental
retardation and an increase in T3 but normal T4 and TSH
. In other words, a normal functioning pituitary gland
and thyroid gland producing enough T4, does not exclude
other organs having insufficient hormones due to
hormone transporter problems.
Numerous studies have provided evidence that
polyhalogenated aromatic hydrocarbons (PHAHs) and their
metabolites affect the thyroid hormone system: 1) They
may interfere directly with the thyroid gland, 2) with
thyroid hormone metabolizing enzymes
(uridinediphosphate-glucuronyl transferases), iodothyronine
deiodinases, and sulfotransferases which are located in
the liver and the brain, 3) by interfering with the plasma
transport system of the thyroid hormone by competing
with plasma transthyretin (TTR) binding sites in
animals, in humans this TTR is less important and TBG is
the main transporter in plasma  and 4) influence
membrane transporter proteins, that are specific for
different target organs . PBDEs have structural
similarities to T3 and T4, therefore it has been hypothesized
that PBDEs might interfere with the transport and
metabolism of T3 and T4 . Another possibility is the
upregulation of type 1 deiodinase, which is involved in the
deiodination of T4 to T3 and reverse T3 .
Doucet  published a sharp increase in the content
of PBDEs in fetal livers of human fetuses after elective
abortions in early to mid-gestation and in the placenta.
Total PBDEs increased over time from 284 ng/g lipid in
1998 to 1607 ng/g lipid in 2006. Main found significant
higher PBDE-levels in the breastmilk of mothers whose
newborn sons had cryptorchidism .
Effects on the thyroid homeostasis in relation to
PBDEs have been seen in animal studies. In a study of
mink ingesting PBDE via their feed, a decrease in T3
was seen . A decrease in T3 and T4 was also seen in
fetuses of pregnant sheep who were exposed to BDE-47
. PBDEs have been shown to decrease T4 and free
T4 in animals. T3 was also decreased in some studies,
but to a lesser extent than total T4 [40,41] . Animals
dont have TBG like humans for the transport of T4
and T3 in blood.
In a study on 23 subjects living close to an electronic
waste and 26 control, higher TSH levels were found in
the studied subjects, who had higher PBDE levels in their
serum compared to a control group (382 ng/g lipids
versus 158 ng/g lipids) . In a small study investigating 11
electronic dismantling workers, no significant effects
were mentioned related to TSH, T3 or T4 .
No association of BDE-47 or PCB-153 with TSH or
thyroid hormone concentrations were found in 110 men
with high consumption of fish from the Baltic Sea .
In a later study of 182 females however, a relationship
between PCB-153 concentrations in plasma and T3
levels was seen .
Thus, besides the remodelling effects of tissues by
PBDEs, as described by Main  in the form of
cryptorchidism during prenatal life, health problems in later
life are also possible and we speculate that these health
problems are caused by effects on peripheral target
organs, maybe through thyroid hormone transporter
disruption. The background levels of the PBDEs are rather
high in the Netherlands compared to other European
countries but still ten times lower than in the US. An
enhanced effect due to multiple exposures to dl-PCBs as
well might additively worsen the situation.
In conclusion, the thyroid hormone system in Dutch
adolescents is influenced by current levels of dl-PCBs
and PBDEs. Most plausible is a toxic effect in the
peripheral target organs, involving the membrane
transporter proteins. A disruption may be compensated, but it is
questionable if this compensation is sufficient for all
organs depending on thyroid hormones. Pathology in
some target organs may be present. Quantification of
this compensation is currently very difficult.
ML, GtT, TV, WvA, TvT and JK were equally involved
in the set-up and execution of the epidemiological part
of the study, while ML and GtT should be considered as
first authors. ML, KO and PdV were all involved in the
study and performed the measurements of the
chemicals. AB, MKvK, CM, HR and GC were involved in
preparing the paper.
I-TEQ: International Toxic Equivalency factor; PCB: polychlorinated biphenyls;
PCDD: polychlorinated dibenzo-p-dioxins; PCDF: furans = polychlorinated
dibenzo-furans; PBDE: polybrominated diphenylether; HBCD:
hexabromocyclododecane; TBBPA: tetrabromobisphenol A; DBDE:
decabromodiphenyl ether; FT4: Free thyroxine; T3: triiodothyronine; T4:
thyroxine; TBG: thyroxine-binding globulin; TSH: thyroid stimulating
hormone; PCB: polychlorinated biphenyls; BDE 99: brominated diphenyl
ether; MCT 8: monocarboxylate transporter 8
The work has been funded by the EU FP6 coordination action HENVINET,
contract no 037019.
The authors wish to thank the participants of the study, and their parents,
for their cooperation; Dr. J. Oosting for his help with the statistics; and P.
Sern, F. vd Wielen and J. Parsons of the laboratory of the Institute for
Biodiversity and Ecosystem Dynamics for their help with the chemical
measurements. We are indebted to Dr. Matthijs Westra paediatrician for his
help to investigate the children in the Zaans Medical Centre De Heel
Thanks also to Scott Randall who did the language review.
The study was also supported by E.C. grant: OBELIX : 227391
This article has been published as part of Environmental Health Volume 11
Supplement 1, 2012: Approaching complexities in health and environment.
The full contents of the supplement are available online at http://www.
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