R E S EAR CH Open Access

Neurobehavioral function and low-level exposure

to brominated flame retardants in adolescents:

a cross-sectional study

Michał Kiciński1, Mineke K Viaene2, Elly Den Hond3, Greet Schoeters3,4, Adrian Covaci5, Alin C Dirtu5, Vera Nelen6,

Liesbeth Bruckers7

, Kim Croes8, Isabelle Sioen9, Willy Baeyens8, Nicolas Van Larebeke10 and Tim S Nawrot1,11*

Abstract

Background: Animal and in vitro studies demonstrated a neurotoxic potential of brominated flame retardants, a

group of chemicals used in many household and commercial products to prevent fire. Although the first reports of

detrimental neurobehavioral effects in rodents appeared more than ten years ago, human data are sparse.

Methods: As a part of a biomonitoring program for environmental health surveillance in Flanders, Belgium, we

assessed the neurobehavioral function with the Neurobehavioral Evaluation System (NES-3), and collected blood

samples in a group of high school students. Cross-sectional data on 515 adolescents (13.6-17 years of age) was

available for the analysis. Multiple regression models accounting for potential confounders were used to investigate

the associations between biomarkers of internal exposure to brominated flame retardants [serum levels of

polybrominated diphenyl ether (PBDE) congeners 47, 99, 100, 153, 209, hexabromocyclododecane (HBCD), and

tetrabromobisphenol A (TBBPA)] and cognitive performance. In addition, we investigated the association between

brominated flame retardants and serum levels of FT3, FT4, and TSH.

Results: A two-fold increase of the sum of serum PBDE’s was associated with a decrease of the number of taps

with the preferred-hand in the Finger Tapping test by 5.31 (95% CI: 0.56 to 10.05, p = 0.029). The effects of the

individual PBDE congeners on the motor speed were consistent. Serum levels above the level of quantification

were associated with an average decrease of FT3 level by 0.18 pg/mL (95% CI: 0.03 to 0.34, p = 0.020) for PBDE-99

and by 0.15 pg/mL (95% CI: 0.004 to 0.29, p = 0.045) for PBDE-100, compared with concentrations below the level

of quantification. PBDE-47 level above the level of quantification was associated with an average increase of TSH

levels by 10.1% (95% CI: 0.8% to 20.2%, p = 0.033), compared with concentrations below the level of quantification.

We did not observe effects of PBDE’s on neurobehavioral domains other than the motor function. HBCD and TBBPA

did not show consistent associations with performance in the neurobehavioral tests.

Conclusions: This study is one of few studies and so far the largest one investigating the neurobehavioral effects

of brominated flame retardants in humans. Consistently with experimental animal data, PBDE exposure was

associated with changes in the motor function and the serum levels of the thyroid hormones.

Keywords: Brominated flame retardants, PBDE, TBBPA, HBCD, Neurotoxicity, Neurobehavioral function, Cognitive

function, Cognition, Adolescents

* Correspondence: tim.nawrot@uhasselt.be 1

Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium

11School of Public Health, Occupational and Environmental Medicine,

KULeuven, Leuven, Belgium

Full list of author information is available at the end of the article

© 2012 Kiciński et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative

Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and

reproduction in any medium, provided the original work is properly cited.

Kiciński et al. Environmental Health 2012, 11:86

http://www.ehjournal.net/content/11/1/86
Background

Brominated flame retardants (BFR) are chemicals widely

used in a variety of household and commercial products

including plastics, electric equipment, textiles, and

polyesters in order to prevent fire [1,2]. Many of them

bioaccumulate in the environment and have been found

in water, air, biota, human tissues, breast milk, and blood

[3-6]. House dust and food represent two important

sources of human exposure [5,7].

A number of animal studies showed effects of a

prenatal and postnatal exposure to BFR on neurodevelopment and were recently reviewed. [8-10] Neurobehavioral effects during juvenile development or

adulthood have been observed in rodents after a brief

postnatal exposure to polybrominated diphenyl ethers

(PBDE) 47 [11,12], 99 [11,13-16], 153 [17], 203 [18],

206 [18], 209 [19-22], the commercial PBDE mixture

DE-71 [23,24], and hexabromocyclododecane (HBCD)

[25,26], a chronic perinatal exposure to PBDE-47

[27,28] and PBDE-99 [29], and an acute prenatal exposure to PBDE-99 [30]. Detrimental effects of PBDE

exposure on neurodevelopment have also been

reported in zebrafish [31,32]. Changes in the motor

activity have been most frequently studied and best

documented [8,10]. Also in vitro studies support the

hypothesis of neurotoxicity of BFR. PBDE congeners

were capable of inducing oxidative stress [33-35] and

apoptosis [33,34] in cultured neurons.

Despite the fact that the first results of the experimental animal studies suggesting a neurotoxic potential of

BFR were available more than 10 years ago, the effects

in humans have not been extensively investigated to

date. Three small prospective studies [36-38] evaluated

the effects of a perinatal exposure to BFR on neurobehavioral function in children. Concentrations of several

PBDE congeners in umbilical cord blood of newborns

showed an association with indicators of neurodevelopment in early childhood. [37] In another study [36], consistent neurodevelopmental effects at the age of 8–

12 months of the exposure measured by breast milk

PBDE concentrations were not observed. Roze et al. [38]

reported both negative and positive neurobehavioral

effects of a prenatal exposure to HBCD and several

PBDE congeners among 5–6 year-old children. In a

cross-sectional study on older adults [39], PBDE’s measured in the serum were not associated with performance in cognitive tasks. All associations reported in

these studies were investigated using less than 150

participants.

The thyroid system is one of the targets of BFR [40].

Experimental animal studies have demonstrated that a

PBDE exposure may result in a decrease of blood thyroxine [22,24,41-45] and triiodothyronine [43,44,46-48]

levels. These effects were observed not only in gestation

and early childhood, but also later in life [41,42]. A disruption of the thyroid system has been suggested as a

mediator of the BFR neurotoxicity [9,49].

We conducted a cross-sectional study of the association between neurobehavioral function and biomarkers

of exposure to BFR [serum levels of polybrominated

diphenyl ether (PBDE) congeners 47, 99, 100, 153, 209,

hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA)] in a group of Flemish adolescents.

Additionally, we investigated the association between

BFR and the thyroid function as a potential biological

mechanism responsible for the neurotoxicity of these

chemicals.

Methods

Study population and data collection

The study was a part of a biomonitoring program for environmental health surveillance in Flanders, Belgium.

The participants were recruited between 2008 and 2011

in two industrial areas (Genk and Menen) and from the

general population of Flemish adolescents. Participants

were eligible if they studied in the third year of secondary school. Hence, most participants were 14 or 15 year

old, but older students were also allowed in the study.

In the general Flemish population, random sampling

was attained through a multistage sampling design.

In the first step, ten schools (two in each of the five

Flemish provinces) - at least 20 km apart from each

other - were randomly selected. In the second step,

classes were randomly selected within each school and

all pupils in a class were invited until the provided number of participants was reached. The number of participants per province was proportional to the number of

inhabitants in that province (status at 01/01/2006).

In Genk and Menen, study areas were defined based

on environmental data and the location of the industrial

sites. All pupils in the requested age range living within

the selected study area were eligible. Names and

addresses were attained from the population registry. In

Genk 54% of the adolescents were invited via a letter

send to the home address and 46% during a home visit.

In Menen, all participants were invited via a letter send

to the home-address. Due to a small response, 30% of

the invited children were contacted again via schools

and 9% via a home visit.

Two weeks before the study session, subjects received

two questionnaires to fill in, one for themselves and one

for their parents. The questionnaire for adolescents

included information about their exercising habits,

amount of time spent using a computer, alcohol use, and

smoking. Questions about the socioeconomic status,

passive smoking and eating habits were included in the

questionnaire for parents. The study session including

an administration of the neurological tests, a collection

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of a blood sample, and a measurement of the length and

the weight was around 1 hour long. Each subject

received a 10 Euro voucher for the participation. Both

parents and teenagers provided informed consent for

participation. The study was approved by the Ethical

Committee of the University of Antwerp.

The response rate equaled 22.1% in the general

Flemish population, 34.3% in Genk and 22.5% in Menen.

A non-responder analysis performed in a group of 106

adolescents (30 participants and 76 non-participants)

did not reveal differences in socio-economic status indicators type of education (general secondary education

versus other, p = 0.58), education of the father (higher

education vs not, p = 0.99), or education of the mother

(higher education vs not, p = 0.22) between participants

and non-participants. The proportion of girls was higher

among the participants (83.3% vs. 61.8% in non-participants, p = 0.03), but an equal distribution between boys

and girls was a stratification criterion in the recruitment

strategy. 606 adolescents participated in the study. Blood

measurements were not available for three participants,

and four participants did not complete any of the neurobehavioral tests. Additionally, for 84 out of the

remaining 599 participants information on at least one

of the covariates used in the analysis was missing. 515

subjects who completed at least one neurobehavioral test

and for whom information about the covariates and

serum BFR levels was available, were used in the analysis

(see Table 1). This group consisted of 163 adolescents

from Genk, 178 from Menen, and 174 from the general

Flemish population.

Neurobehavioral tests

Neurobehavioral Evaluation System (NES) is a computerized battery of tests developed to study the neurological effects of an exposure to environmental agents

[50]. NES has been used in a number of studies investigating the neurobehavioral impact of neurotoxicants and

dose–response relationships with intensity of exposure

were reported [51]. In our study, we used four tests from

the NES-3 version of the test battery [52] (see Figure 1).

In the Continuous Performance test, a series of letters

is displayed on the screen, one at a time, and each for

approximately 200 msec. The task is to immediately respond to the letter S, and not to other letters, by pressing the spacebar. A new letter appears each 1000 msec.

In total, the letter S appears 60 times. The mean reaction

time for responding to the target letter in msec, the

number of errors of omission, i.e., the number of times

that a subject did not react within 1200 msec, the number of errors of commission, i.e., the number of

responses when the letter S was not displayed, were used

as the measure of performance. The test evaluates sustained attention. It showed a good test-retest reliability

Table 1 Descriptive statistics

N = 515A

Boys 271 (52.6%)

Age, years 14.9 (0.7)

BMI, kg/m2 20.4 (3.1)

Type of education – general secondary 290 (56.3%)

The highest level of education of parents

no diploma 22 (4.3%)

9 grades 52 (10.1%)

12 grades 163 (31.7%)

College of university diploma 278 (54%)

Parents owning the house 456 (88.5%)

Current smoking 65 (12.6%)

Passive smokingB 82 (15.9%)

Alcohol use at least once a month 129 (25%)

Number of hours a week using computer

< 2 50 (9.7%)

2-9 271 (52.6%)

10-19 147 (28.5%)

≥ 20 47 (9.1%)

Fish consumptionC

Low 224 (43.5%)

Average 186 (36.1%)

High 105 (20.4%)

Physical activity in leisure time at least once a week 405 (78.6%)

Blood lipids, mg/dl 448.9 (72.9)

Blood lead, μg/dl 1.4 (0.7 to 2.9)

Sum of serum PCB 138, 153 and 180, ng/L 171.6 (58 to 445)

Thyroid hormones serum levels

FT3, pg/mL 4.15 (0.53)

FT4, ng/dL 1.24 (0.17)

TSH, μU/mL 2.15 (0.99 to 4.45)

Neurobehavioral parameters

Continuous Performance, reaction time, msec,

N = 489

409.2 (41.8)

Continuous Performance, errors of omission, N = 489 2.3 (2.7)

Continuous Performance, errors of commission,

N = 489

5.6 (3.5)

Digit Symbol, sec, N = 340 98.3 (17.7)

Digit Span Forward, N = 511 5.6 (1.03)

Digit Span Backward, N = 499 4.49 (1.01)

Finger Tapping, preferred hand, N = 511 293.7 (40.2)

Finger Tapping, non-preferred hand, N = 509 258.6 (33.8)

Arithmetic mean (standard deviation) is given for the continuous variables

used on their original scale and geometric mean (5th to 95th percentile) for the

logarithmically transformed continuous variables. Count (percent) is given for

the categorical variables.

A

Participants for whom information about the covariates, brominated flame

retardants blood levels, and at least 1 neurobehavioral measure was available.

B

At least 1 family member smoking inside the house.

C

Based on two questions about the amount of warm and cold fish eaten per

week. Low corresponds to less than 20 g, middle to 20–25 g and high to more

than 25 g per day.

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in a group of patients directed to a neuropsychological

examination [51].

In the Digit-Symbol test, a row of 9 symbols paired

with 9 digits is displayed at the top of the screen. The

same 9 symbols but in a different order are shown at the

bottom. When a digit is displayed, the task is to indicate

the symbol, which is paired with this digit, from the bottom row. A new digit appears only after the correct

symbol has been indicated. In total, 27 digits are displayed. The total time needed to complete the test measured in seconds describes the performance. The test is

characterized by a satisfactory reliability [52]. In a part

of the study area, a different test was administered instead of the Digit-Symbol test. As a result, the results of

this test were only available for a group of 341 participants from Genk and Menen.

The Digit Span test consists of two parts. In the first

part, a subject hears a sequence of digits. The task is

to reproduce them. In case of a correct answer, a one

digit longer sequence is presented. In case of a mistake,

a sequence of the same length is presented. When two

incorrect answers in a row are given, the first part of

the test finishes. The second part is the same as the

first one, but the sequences are reproduced in the reverse order. Digit Span Forward is the maximum span

reproduced in the first part. Digit Span Backward is

the maximum span reproduced in the reverse order.

The first part of the test assesses the working memory

span. Good performance in the second part requires

both the ability to hold and manipulate information. In

a part of the study area, the Digit Span test was administered using computers with touch screens. In this

case the task was to indicate the digits on the screen,

not using the keyboard. In order to account for a possible effect of the way the test was administered, an indicator variable was included in the regression models

for this test.

In the Finger Tapping test a subject presses the spacebar as many times as possible during a trial of 10 sec.

The first part of the test consists of 4 trials with the preferred-hand. The second part consists of 4 trials with the

non-preferred hand. The summary measures are the

total number taps with the preferred-hand and the total

number of taps with the non-preferred hand. The test

measures the manual motor speed.

Blood samples analysis

PBDE congeners 28, 47, 99, 100, 153, 154, 183, and 209,

HBCD, and tetrabromobisphenol A (TBBPA) were measured in the serum according to the method described

by Covaci and Voorspoels [53]. Briefly, solid phase extraction was performed to prepare the samples. The eluate was purified on acid silica. The extract was further

analyzed by gas chromatography mass spectrometry in

electron capture negative ion mode using a 25 m ×

0.22 mm × 0.25 μm HT-8 column.

Characteristics of the distributions of the BFR are

shown in Table 2. PBDE congeners 28, 154 and 183 for

which less than 5% of the observations had a concentration higher than the limit of quantification (LOQ), were

not used in the analysis. For PBDE 47, 99, 100, 153, and

209 binary exposure indicators were used with the LOQ

values as thresholds. The logarithm of the sum of PBDE

47, 99, 100, 153 was used as a measure of the total longterm PBDE exposure. In the calculation of the sum, the

values below LOQ were replaced by LOQ/2.

Concentrations of PCB congeners in the serum were

determined using the same method as for the BFR. The

sum of PCB 138, 153, and 180 transformed logarithmically was used as an indicator of the PCB exposure. Lead

was measured in the whole blood as described by

Schroijen et al. [54]. Blood lipids were measured

Figure 1 An overview of the neurological tests used in the study.

Table 2 Concentrations of polybrominated flame

retardants in serum (ng/L)

LOQ Median P75 P95 Max

BDE28 2 <LOQ <LOQ <LOQ 24

BDE47 3 <LOQ 3 9 104

BDE99 3 <LOQ <LOQ 3 12

BDE100 2 <LOQ <LOQ 2 42

BDE153 2 2 3 8 24

BDE154 2 <LOQ <LOQ <LOQ 6

BDE183 2 <LOQ <LOQ <LOQ 5

BDE209 25 <LOQ <LOQ 53 325

HBCD 30 <LOQ <LOQ 59 234

TBBPA 15 <LOQ <LOQ 22 186

SUM PBDEA 7 10 21 125

LOQ – limit of quantification. A

The sum of PBDE congeners 47, 99, 100, and 153. In the calculation, values

lower than LOQ were replaced by LOQ/2.

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graphimetrically. Thyroid hormones FT3, FT4 and TSH

were measured by competitive immune assays.

Statistical analysis

We used SAS software version 9.2 (SAS Institute Inc,

Cary, NC) for all analysis. Continuous positive-value

variables with a right-skewed distribution were logarithmically transformed. Normal quantile plots of the residuals were used to examine the normality assumption

for all linear models. For the individual PBDE congeners,

HBCD and TBBPA the effects of the concentrations

above the LOQ compared to the concentrations below

the LOQ were estimated. The sum of PBDE’s was transformed logarithmically, and the effect of its two-fold increase was estimated.

In all the models investigating the effects on the neurobehavioral parameters, we corrected for age of a child,

gender, type of education (general secondary education

versus other), the highest level of education attained by

either of the parents (using three indicator variables),

whether or not the parents owned the house, smoking,

passive smoking, and blood lipids. Models evaluating the

effects on the number of digits reproduced in the Digit

Span test were also corrected for the method of test administration (touch screen versus keyboard). Additionally, we corrected for the covariates BMI of a child,

physical activity in leisure time at least once a week,

computer use, alcohol use at least once a month,

fish consumption, the logarithm of blood lead and

the logarithm of serum PCB’s 138, 153 and 180, which

were selected using a stepwise regression procedure with

p = 0.15 for entering and p = 0.10 for remaining in the

model. In the models investigating the effects of BFR on

FT3, FT4, and TSH levels, we corrected for age, gender,

BMI, and blood lipids in all models. Other variables

mentioned above besides computer use were included in

the model based on a stepwise regression procedure

with p = 0.15 for entering and p = 0.10 for remaining in

the model.

Finally, we investigated whether the effects of BFR

were modified by gender by including the interaction

term in the regression model.

Table 3 Determinants of the neurological parameters

Continuous performance (N = 489) Digit symbol (N = 340) Digit span Finger tapping

Reaction time

(msec)A

Errors of

omissionB

Errors of

commissionB

Total latency

(sec)A

ForwardA

(N = 511)

BackwardA

(N = 499)

Preferred

handA

(N = 511)

Nonpreferred

handA

(N = 509)

Boys 0.43 (0.12)** 0.29 (0.06)** 4.12 (1.82)* 9.71 (3.59)** 5.53 (3.09)

Age, 1 year

increase

−8.57 (2.79)** −0.14 (0.08) −0.15 (0.04)** −5.21 (1.21)** 5.47 (2.2)*

BMI, IQR

increase =

3.4 kg/m2

0.06 (0.03) 2.22 (0.97)*

Education

type – general

−15.09 (3.76)** −0.54 (0.11)** −0.17 (0.06)** −9.73 (1.82)** 0.44 (0.09)** 0.53 (0.09)** 8.12 (3.05)**

Parents: no

diplomaC

9 gradesC −14.26 (5.7)*

12 gradesC −0.17 (0.1)

Alcohol use 0.11 (0.07) 0.19 (0.1)

Computer useD −5.26 (2.37)*

Physical activity −10.24 (4.57)* 14.72 (4.23)** 7.47 (3.61)*

Blood lead,

2-fold increase

3.58 (1.6)* −0.14 (0.07)

Sum PCB’s,

2-fold increase

−0.14 (0.07)* −0.06 (0.03) 0.14 (0.05)** 0.09 (0.05) 4.44 (2.07)* 4.74 (1.79)**

*p < 0.05, **p < 0.01.

A Estimated effect (standard deviation) from a linear model.

B Estimated effect (standard deviation) from a negative binomial model.

C Reference category: college or university diploma.

D

The effect of a one level increase of category.

Stepwise regression estimates of the effects of covariates on the neurological parameters with p = 0.15 for entering and p = 0.10 for remaining in the model. All

covariates included in one of the models are shown in the table. The set of considered covariates included: gender, age, BMI, type of education (general

secondary education versus other), the highest level of education of parents (three indicator variables), whether or not the parents owned the house, smoking,

passive smoking, alcohol use at least once a month, computer use, fish consumption, physical activity in leisure time at least once a week, the logarithm of blood

lead and the logarithm of serum PCB’s 138, 153, and 180.

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Table 4 Estimated effects of serum levels of brominated flame retardants on performance in the Continues Performance, Digit-Symb

Continuous Performance (N = 489) Digit Symbol (N = 340) 

Reaction time (msec)A Errors of omissionB Errors of commissionB Total latency (sec)A ForwardA (N = 51

Effect 95% CI Effect 95% CI Effect 95% CI Effect 95% CI Effect 95% C

PBDE47 3.45 −4.88 to 11.78 −10% −29.9 to 15.6% 6.2% −6.2 to 20.1% −1.19 −5.57 to 3.2 −0.09 −0.29 to 

PBDE 99 −5.39 −19.85 to 9.08 −16.3% −46.4 to 30.8% 12.9% −8.6 to 39.5% −1.35 −8.94 to 6.24 0.09 −0.25 to 

PBDE100 7.61 −5.94 to 21.16 −5.8% −37.2 to 41.4% −3.2% −21 to 18.5% 1.98 −5.6 to 9.56 −0.26 −0.57 to 

PBDE153 5.09 −2.76 to 12.95 −19.3% −36.4 to 2.3% −2% −12.8 to 10.2% −1.34 −5.46 to 2.77 −0.09 −0.28 to 

PBDE209 −1.2 −14.49 to 12.1 −17.7% −45.1 to 23.4% 1.4% −16.9 to 23.7% 2.08 −4.07 to 8.23 0.06 −0.26 to 

HBCD −3.53 −18.72 to 11.67 27.8% −17.5 to 97.9% 21.8% −2.5 to 52.2% −0.44 −6.59 to 5.72 0.13 −0.22 to 

TBBPA −2.25 −17.28 to 12.77 −9.3% −43 to 44.2% −17.7% −34.7 to 3.9% −2.48 −10.36 to 5.41 0.03 −0.32 to 

SUM PBDE 2.12 −2.9 to 7.13 −6.6% −19.9 to 8.9% 0.7% −6.6 to 8.6% −0.39 −3.04 to 2.26 −0.01 −0.13 to 

A A linear model.B A negative binomial model (estimated change in%).

For the individual PBDE congeners, HBCD, and TBBPA the effects of levels above the LOQ were estimated. Sum of serum PBDE’s 47, 99, 100, and 153 was logarithmically transforme

increase were estimated.All models were adjusted for gender, age, type of education (general secondary education versus other), the highest level of education of parents (using three indicator variables), wthe house, smoking, passive smoking, and blood lipids. Models evaluating the effects on the number of digits reproduced in the Digit Span test were in addition adjusted for the m

screen verses keyboard). Additionally, BMI, physical activity in leisure time at least once a week, computer use, alcohol use at least once a month, fish consumption, the logarithm oserum PCB’s 138, 153, and 180 were included in the model based on the stepwise regression procedure with p = 0.15 for entering and p = 0.10 for remaining in the model.
Results

Characteristics of the study population

The characteristics of the study group are given in

Table 1. The adolescents (52.6% boys) were between

13.6 and 17 years of age, and the mean age equaled

14.9 years. A majority of the participants (54%) had at

least one parent who graduated from a college or a university. A summary of the results obtained in the neurobehavioral tests is given in Table 1.

Determinants of neurobehavioral function

Estimates of the effects of the covariates on the neurobehavioral parameters are shown in Table 3. Gender, age,

type of education, parental education, and physical activity were the most important determinants of the performance in the tests.

Associations between BFR and the neurobehavioral

function

We did not find any significant associations between

serum levels of BFR and performance in the Continuous Performance, Digit-Symbol or Digit Span tests

(Table 4). However, PBDE’s were associated with a deterioration of the performance in the Finger Tapping

test in the preferred-hand condition (Figure 2). In the

continuous analysis, a two-fold increase of the sum of

serum PBDE’s was associated with a decrease of the

number of taps with the preferred-hand by 5.31 (95%

CI: 0.56 to 10.05, p = 0.029). The model explained

9.85% of the total variability and 0.87% of the variability

could be attributed to the sum of serum PBDE’s. Concentrations above LOQ were associated with an average

decrease of 7.04 taps (95% CI: -0.78 to 14.87; p = 0.078)

for serum PBDE-47, 12.13 (95% CI: -1.3 to 25.57; p =

0.078) for serum PBDE-99, 12.43 (95% CI: -0.03 to

24.89; p = 0.051) for serum PBDE-100, and 8.43 (95%

CI: 1.01 to 15.86; p = 0.026) for serum PBDE-153. The

associations between serum PBDE’s and the number of

taps with the non-preferred hand were usually consistent (negative association), but did not reach the level of

significance. Serum HBCD and TBBPA levels were not

significantly associated with performance in the Finger

Tapping test.

Also after adjusting for the number of errors of

omission and commission, none of the BFR exposure

indicators was significantly related with the mean reaction time in the Continuous Performance test. Exposure to BFR did not show negative associations with

performance in the Continuous Performance test in

analysis stratified by period (Figure 3). Gender did not

significantly modify the association between the sum

of PBDE’s and the number of taps with the preferred

hand (p = 0.25).

Associations with the FT3, FT4, and TSH levels

The estimated associations between BFR and FT3, FT4,

and TSH serum levels after correction for possible confounders are shown in Figure 4. Serum levels above

LOQ were associated with an average decrease of FT3

level by 0.18 pg/mL (95% CI: 0.03 to 0.34, p = 0.020)

for PBDE 99 and by 0.15 pg/mL (95% CI: 0.004 to 0.29,

p = 0.045) for PBDE-100. For the other PBDE congeners

the associations had the same direction but were not

statistically significant. We did not observe significant

associations between PBDE congeners and FT4 levels.

PBDE-47 level above LOQ was associated with an average increase of TSH levels by 10.1% (95% CI: 0.8% to

20.2%, p = 0.033). The other PBDE congeners were not

significantly associated with TSH.

The continuous analyses did not show significant associations between PBDE’s and the thyroid hormone levels.

For a two-fold increase of the sum of serum PBDE’s,

FT3 was estimated to decrease by 0.05 pg/mL (95% CI:

-0.01 to 010, p = 0.10), FT4 to increase by 0.017 ng/dL

(95% CI: -0.003 to 0.032, p = 0.10), and TSH to increase

by 3.9% (95% CI: -1.5% to 9.6%, p = 0.16). We did not

observe any significant effects of HBCD or TBBPA on

the hormone levels. The adjustment for the levels of the

Figure 2 Estimated effects of the serum levels of brominated

flame retardants on the performance in the Finger Tapping

test. For the PBDE congeners, HBCD, and TBBPA the effects of levels

above the LOQ were estimated. Sum of PBDE’s 47, 99, 100, and 153

was logarithmically transformed and the effects of its two-fold

increase were estimated. All models were adjusted for: gender, age,

type of education (general secondary education versus other), the

highest level of education of parents (using three indicator

variables), whether or not the parents owned the house, smoking,

passive smoking, and blood lipids. Additionally, BMI, physical activity

in leisure time at least once a week, computer use, alcohol use at

least once a month, fish consumption, the logarithm of blood lead

and the logarithm of serum PCB’s 138, 153, and 180 were included

in the model based on the stepwise regression procedure with

p = 0.15 for entering and p = 0.10 for remaining in the model.

Kiciński et al. Environmental Health 2012, 11:86 Page 7 of 12

http://www.ehjournal.net/content/11/1/86
thyroid hormones did not substantially change the estimate of the effect of the sum of PBDE’s on the number

of taps with the preferred-hand.

Discussion

Consistently with the experimental animal studies demonstrating that exposure to PBDE’s during gestation and

early childhood affects the motor function [11-22,26-28],

we observed negative associations between the serum

levels of these BFR and motor speed of the preferred

hand in adolescents. The associations between PBDE’s

and the second indicator of the motor function, the

number of taps with the non-preferred hand were not

significant but showed the same trend. The nonpreferred hand test is performed after the preferred hand

test in the Finger Tapping test. Our results resemble

observations from the experimental animal studies in

which a decrease of the motor activity related to PBDE

exposure was present only in the beginning of the tests

[11,14-21,25]. We did not observe negative associations

between BFR and neurobehavioral domains other than

the motor function.

Human data on the neurobehavioral effects of BFR are

scarce. In the United States, a prenatal PBDE exposure

was inversely associated with the level of mental development at the age of two and inteligence at the age of

two and three [37]. In a Dutch study, a prenatal exposure to PBDE-47 and PBDE-99 showed a negative association with sustained attention and PBDE-153 with

verbal memory measured at the age of five and six

[38]. In contrast to these two studies, we conducted a

cross-sectional study and focused on older children.

The serum levels of PBDE’s were not associated with

neurobehavioral outcomes in a cross-sectional study of

older adults in New York [39]. To our knowledge, the

neurobehavioral effects in adolescents have not been

studied yet.

Higher PBDE-99 and PBDE-100 serum levels were significantly associated with a lower level of serum FT3,

and the results for the other PBDE congeners showed

the same tendency. A negative association between a

PBDE exposure and the triiodothyronine concentration

was also seen in some other epidemiological studies

[55,56]. Consistently with the effects on FT3, most of

the indicators of exposure to PBDE’s were positively

related with TSH levels, although only for PBDE-47 the

level of significance was reached.

Contrary to the experimental animal studies [22,24,41-

45], we did not observe a negative association between

PBDE’s and FT4 concentration. This is in agreement

with other epidemiological studies in humans in which

either non-significant associations or significant positive

Figure 3 Estimated effects of the serum levels of brominated flame retardants on the performance in the Continuous Performance

from analysis with stratification by period. For each exposure indicator, the effect on outcome in the first, the second, the third and the

fourth block is shown. Each block consisted of 12 trials. The same modeling strategy as in the analysis without stratification was applied.

Kiciński et al. Environmental Health 2012, 11:86 Page 8 of 12

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associations were obtained [56-59]. The discrepancy between animal and human data can be possibly explained

by high PBDE doses used in the animal studies in which

the effects on thyroxine levels were observed. Although

we observed a positive association between PBDE-47

and TSH, the FT4 levels were not negatively associated

with PBDE’s. A possible explanation is that PBDE’s

may inhibit the deiodinase enzymes which serve to

metabolize thyroxine to triiodothyronine [59], resulting

in an increase in circulating thyroxine and a decrease

in ciruculating triiodothyronine levels.

The biological mechanisms of the effects of PBDE’s on

the thyroid hormones circulating in the blood have not

been fully understood yet. PBDE’s exposure caused

histological and morphological changes in the thyroid

gland in rats indicating its decreased activity [43,60]. It

also strongly upregulated uridinediphosphate-glucuronosyltransferase, an enzyme transforming molecules including thyroid hormones into excretable metabolites

[44,45]. PBDE exposure also resulted in induction of

pentoxy-resorufin-O-deelthylase activity [42,44,45].

Controlling for the thyroid hormone levels did not

substantially change the estimated effects of the sum of

PBDE’s on the motor speed. Besides the effects on the

thyroid function, a disturbance of the cholinergic system

may be a pathway by which PBDE’s affect the motor

function. A neonatal PBDE exposure resulted in reduced

or hypoactive behavioral responses to cholinergic agonist

nicotine [19,61] and a decreased amount of nicotine

receptors in adult rodents [17,62]. PBDE’s are also capable to disrupt calcium homeostasis in the brain, cause

oxidative stress and apoptotic cell death [9,49].

Elimination of PBDE congener from human tissues

depends strongly on the level of bromination [63-65].

The half-life time in human tissues has been estimated

to be around 2 weeks for PBDE-209 [63-65], between a

year and a few years for PBDE-47, PBDE-99, and PBDE100 [63,65], and may be even longer for PBDE-153

[63,65]. Therefore, serum concentration of PBDE’s 47,

99, 100, 153, and the sum of these congeners’ concentration indicate to a large extent a long-term exposure. The

estimated HBCD total body half-life time equaled 64 days

[63]. Most of TBBPA was excreted from the body of rat

within a few days after administration [66]. The serum

BFR levels at adolescence which we used as exposure

indicators, were unlikely to be strongly affected by the

exposure during gestation and the first years of life,

which may be a period of a particular susceptibility to

the neurotoxicity of BFR.

The main limitation of our study was a large number

of observations for which PBDE levels took values below

the limit of quantification. In order to deal with this

problem, we used binary exposure indicators. However,

the limits of quantification which we used to create the

categories did not represent critical values separating

safe and dangerous exposure levels. This dichotomization of continouos exposure indicators and a possible

missclassification due to the use of thresholds which did

not have biological relevance might have substantially

reduced the statistical power. For 222 participants the

Figure 4 Estimated effects of the serum levels of brominated

flame retardants on serum FT3, FT4, and TSH concentrations.

For the PBDE congeners, HBCD, and TBBPA the effects of levels

above the LOQ were estimated. Sum of PBDE’s 47, 99, 100, and 153

was logarithmically transformed and the effects of its two-fold

increase were estimated. All models were adjusted for: gender, age,

BMI and blood lipids. Additionally, type of education (general

secondary education versus other), the highest level of education of

the parents (using three indicator variables), whether or not the

parents own the house, smoking, passive smoking, physical activity,

alcohol use, fish consumption, BMI, the logarithm of blood lead and

the logarithm of the sum of serum PCB’s 138, 153 and 180 were

included in the model based on the stepwise regression procedure

with p = 0.15 for entering and p = 0.10 for remaining in the model.

Kiciński et al. Environmental Health 2012, 11:86 Page 9 of 12

http://www.ehjournal.net/content/11/1/86
levels of both BDE-47, BDE-99, BDE-100, and BDE-153,

were lower than the limit of quantification. However, the

variability in the sum of these congeners observed in the

rest of the participants made it an interesting measure of

an overall exposure to PBDE’s. Replacing the levels

below LOQ with the constant value of LOQ/2 in the calcuation of the sum introduced some measurement error.

This error might have lead to an underestimation of the

effect of an overall PBDE exposure.

Another disadvantage of our study is that the only aspect of the motor function we investigated was the manual motor speed, and that we assessed it only with one

test. Although finger tapping is regarded a reliable measure of the motor speed [67,68], a more extended evaluation is needed to verify our findings and investigate the

effects of PBDE’s on other aspects of the motor function

than the manual motor speed.

Although we corrected for a number of potential confounders, we can not exclude that the associations we

observed resulted from some source of confounding we

failed to account for. Furthermore, a cross-sectional nature of our study does not allow to draw causal conclusions. We can not exclude the possibility that children

with poor motor capabilities chose activities involving

BFR exposure, which resulted in higher blood levels of

these toxicants. Similarly, we can not be sure that the

BFR exposure was a causing factor in the association between the toxicants and the thyroid function we

observed. Our study had a fairly low response-rate.

However, the comparison of socioeconomical status

indicators between a subgroup of participants and nonparticipants did not reveal evidence of a selection bias.

Conclusions

Our study is one of few studies and so far the largest

one investigating the neurobehavioral effects of BFR in

humans. Low-level PBDE exposure was associated with

changes in the motor function and serum levels of FT3

and TSH. Our observations need to be further elucidated in other age groups preferably using prospectively

designed studies.

Abbreviations

PBDE: Polybrominated diphenyl ether; HBCD: Hexabromocyclododecane;

TBBPA: Tetrabromobisphenol A; BFR: Brominated flame retardants; LOQ: Limit

of quantification.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

EDH, GS, KC, LB, MK, MV, NVL, TN, and WB designed the study. EDH, GS, IS,

NVL, and VN did the field work. AC and AD analyzed BFR levels. LB, MK, and

TN performed statistical analysis. MK drafted the manuscript. All authors

critically revised the manuscript.

Acknowledgment

The study was commissioned and financed by the Ministry of the Flemish

Community (Brussels, Belgium) and FWO grants: G.0.873.11.N.10 / 1.5.234.11.

N.00. Michał Kiciński has a Ph.D. and Isabelle Sioen a post-doctoral fellowship

of the Research Foundation – Flanders (FWO).

Author details

1

Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium.

2

Department of Neurology, Sint Dimphna Hospital, Geel, Belgium. 3Flemish

Institute for Technological Research, Environmental Risk and Health, Mol,

Belgium. 4

Department of Biomedical sciences, University of Antwerp,

Antwerp, Belgium. 5

Toxicological Center, University of Antwerp, Antwerp,

Belgium. 6Department of Health, Provincial Institute for Hygiene, Antwerp,

Belgium. 7

Interuniversity Institute for Biostatistics and Statistical

Bioinformatics, Hasselt University, Diepenbeek, Belgium. 8

Department of

Analytical and Environmental Chemistry, Brussels Free University (VUB),

Brussels, Belgium. 9

Department of Public Health, Ghent University, Ghent,

Belgium. 10Department of Radiotherapy and Nuclear Medicine, University

Ghent, Ghent, Belgium. 11School of Public Health, Occupational and

Environmental Medicine, KULeuven, Leuven, Belgium.

Received: 3 July 2012 Accepted: 29 October 2012

Published: 14 November 2012

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doi:10.1186/1476-069X-11-86

Cite this article as: Kiciński et al.: Neurobehavioral function and low-level

exposure to brominated flame retardants in adolescents: a crosssectional study. Environmental Health 2012 11:86.

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