Impact of Brominated POPs on the Neurodevelopment and Thyroid Hormones of Young Children in an Indoor Environment — A Review

The goal of this report is to evaluate brominated persistent organic pollutants (POPs) in the indoor air and dust to further assess their health effects on thyroid hormones and neurodevelopment in infants, toddlers, and young children. This category of brominated POPs includes polybrmonated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), polybrominated biphenyls (PBBs), and polybrominated dibenzo-p-dioxins (PBDD/DFs). These organobromines are lipophilic compounds which resist physical and chemical degradation in the environment and biota, and so easily bioaccumulate in adipose tissue. Brominated POPs, particularly in brominated fire retardants (BFRs) such as PBDEs, HBCDs, and PBBs, are ubiquitous in indoor environments due to their inadvertent release from certain consumer products. Some of these organobromines have been recognized in some in-vitro and in-vivo studies to be neurotoxins and disrupt thyroid hormones, although the evidence from actual epidemiological studies is contradicted and inconsistent, especially for infants, toddlers, and young children, who are particularly vulnerable to these substances as they spend most of their time in the home. This report focuses on exposure to PBDEs, HBCDs, PBBs, and PBDD/DFs in the indoor dust and on the indoor aerosol, to explore their association with human health, particularly the disruption of thyroid hormones and neurodevelopment in early childhood.


INTRODUCTION
Organobromine compounds, including brominated fire retardants (BFRs) and polybrominated dibenzo-p-dioxins/ furans (PBDD/DFs) have emerged as globally persistent organic pollutants (POPs) in the recent years.These brominated POPs have an unusually high resistance to chemical, physical, and biological degradation and are ubiquitous in the environment and they are also easily bioaccumulated at the biota (de Boer et al., 1998;Darnerud et al., 2001;de Wit, 2002).BFRs are included in polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), and hexabromocyclododecanes (HBCDs).Besides the commercial PBDE mixtures, combustion sources have been recognized an important atmospheric PBDE sources (Wang et al., 2010a(Wang et al., , b, 2011)).BDE-209 is the indicatory congener of important combustion sources (Wang et al., 2010a, c).A recent study has showed that for indoor and workplace air, their BDE-209 could be from the evaporative releases of products containing deca-BDE mixture, and the ventilation with outdoor ambient air (Wang et al., 2011).Many reports are also indicated that indoor air may be one of significant sources for the contamination of PBDEs and HBCDs into outdoor air through ventilation system or naturally dispersion (Abdallah et al., 2008;Besis and Samara, 2012;Björklund et al., 2012;Thuresson et al., 2012).Furthermore, boilers fueled with woods also emit PBDEs through their stack flue gases (Wang et al., 2010a), therefore, stoves and fireplaces that fuelled with woods could be a potential PBDE sources to the indoor environment.PBDEs are widely used in a number of commercial products, such as upholstered furniture, textiles, and household electronic equipment, as they improve their resistance to fire (de Wit, 2002).Several studies indicated that brominated POP levels, particularly for PBDEs, in indoor dust were associated with POP levels in breast milk and hormone levels (i.e., thyroid and sex hormones) in male adults (Wu et al., 2007;Meeker et al., 2009;Johnson et al., 2013).
The manufacture of pentaBDEs and octaBDEs has been banned in Europe and voluntarily phased out in USA since 2004 (Costa and Giordano, 2007), but as of 2012, decaBDE is still produced and widely used in most countries outside of Europe.PBBs and certain PBDEs, such as tetra-, penta-, hexa-, and heptaBDEs have been added to the list of POPs at the Stockholm Convention-Annex A (Stockholm Convention, 2012).Despite the bans of PBDE use in many industrialized countries, including European countries and the United States, PBDEs will be continue to be released from exiting products for many years to come (Frederiksen et al., 2009).Owing to current legislative restrictions on PBDEs, the demands for HBCDs have recently increased.Many studies have reported the global bioaccumulation of HBCD in wild animals and humans (de Wit, 2002, Marvin et al., 2011).Recently, HBCDs have been considered to the list at the Stockholm Convention on POPs (Marvin et al., 2011).Little is known about the effects on people with casual as opposed to occupational exposure to PBDD/DFs and their associated health effects, particularly on infants and toddlers.PBDD/DFs are unintentionally released from various combustion processes of textiles, plastics, building materials, and consumer products containing BFRs, and are also present as impurities in technical mixtures of BFRs, particularly in technical mixtures of pentaBDEs, octaBDEs, and decaBDEs (Hanari et al., 2006).PBDD/DFs and BFRs are globally emerging issues in the field of environmental pollution because they are persistent, bioaccumulative, and toxic.
The chemicals in BFRs have long been recognized as lipophilic endocrine disruptors (Legler and Brouwer, 2003) with a potential for bioaccumulation and biomagnification in the food chain (de Boer et al., 1998;Chen et al., 2012).A very important report has revealed that levels of PCDD/Fs, PCBs, and DDTs in breast milk significantly decreased in most developed countries during the last two decades of 20 th Century (1980s-1990s) after governmental regulations have been enacted to reduce their emissions (Noren and Meironyte, 2000).In contrast, levels of PBDEs in human specimens, including breast milk and blood, have dramatically increased in the same period (Noren and Meironyte, 2000;Kalantzi et al., 2004).Recently, an Australian study shows no temporal trend in breast milk levels of HBCD between 1993 and 2009, but PBDE levels in Australian breast milk samples have peak between 2002 and 2004 after which they begin to decline in 2007-2008(Tomes et al., 2012)).In Taiwan, a slight decline of PBDEs in Taiwanese breast milk was found between 2000-2001 and 2007-2008 in our previous study (Koh et al., 2009;Chao et al., 2010a).A declining trend of PBDEs in breast milk may be related to the involuntary phase-out of the use of penta-and octaBDE mixtures since 2005.To date, temporal trends or changes of PBDEs in breast milk have been evaluated and found to be inconsistent with the results in a few studies made after the ban or restriction of the use of PBDEs (Hoopmann et al., 2012;Tomes et al., 2012).In addition, few reports examine the internal doses of PBDD/DFs to explore whether PBDD/DFs act as endocrine disruptors.Scientific concerns regarding contamination of the environment by PBDD/DFs have been raised because these brominated dioxins are considered to be a byproduct of consumer products containing BFRs during the thermal processes (Sakai et al., 2001).
Infants, toddlers, and children are the most vulnerable population.Prenatal and postnatal exposure to BFRs and PBDD/DFs may cause physiological, developmental, or neurobehavioral damage.In recent years, concerns about the adverse health effects on infants, toddlers, and children after they are exposed to brominated POPs have steadily increased.The indoor environment is likely to be an essential exposure route through dust ingestion, hand-to-mouth behaviour, and respiration inhalation, which leads to accumulate PBDEs in human bodies (Stapleton et al., 2012).Toddlers, infants, and children, unlike adults, are likely to spend almost all their time indoors, and due to their behaviour, are likely to ingest even more of these harmful substances, and as they are in a developmental stage, the overall effects are likely to be more serious and long-lasting (Jones-Otazo et al., 2005;Stapleton et al., 2012).Unfortunately, little is known about the specific health effects on infants, toddlers, and children prenatally or postnatally exposed to PBDD/DFs and HBCD.Only a few epidemiological studies have been conducted on the connection between HBCD and breast milk.Currently our greatest concern is that PBDE exposure may cause alterations in thyroid hormone homeostasis and developmental neurotoxicity during these formative years (Chao et al., 2011;Lin et al., 2011;Shy et al., 2011;Shy et al., 2012), but it is still unknown whether higher levels of HBCDs and PBDD/DFs in infants or toddlers may induce adverse health effects, particularly in the disruption of thyroid hormones or interference with neurodevelopment and neurobehavioral development.
In a study done in Greater Boston, a statistically significant and positive correlation was discovered between PBDE concentrations in house dust and in breast milk (Wu et al., 2007).A recent study of family members with nonoccupational exposure to PBDEs suggests that toddlers and children have a higher risk of PBDE exposure and face higher risks of PBDE-related health effects than their parents (Fischer et al., 2006).Toms et al. (2009) investigates concentrations of PBDEs in matched samples of breast milk, dust, and indoor air to determine if levels are based on congener profiles, as the level of bromination increased the contribution of intake decreased via breast milk and increased via dust and the contribution of inhalation to total PBDE intake was minor.The estimated ΣPBDE daily intake from dust for children (49.3 ng/kg b.w./day) during the period from 1-5 years old is six time higher than for adults (7.7 ng/kg b.w./day) because of children's lower body weight and higher dust intake (Lorber, 2008).Toms et al. (2009) calculates that the ΣPBDE daily intake from dust in children ranges between 33 and 118 ng/day but for adults is only from 2.5 to 59 ng/day.

PBDES AND HUMAN HEALTH EFFECTS
PBDEs have been shown to cause reproductive disorders, have neurotoxic and developmental effects, and cause endocrine disruption and thyroid gland dysfunction in animal models (Costa and Giordano, 2007;Tseng et al., 2008;Tseng et al., 2011;Liu et al., 2012).Several epidemiological studies in the general population have strengthened the notion that PBDE exposure can induce adverse health effects (Mazdai et al., 2003;Chao et al., 2007;Main et al., 2007;Herbstman et al., 2008;Lim et al., 2008;Turyk et al., 2008;Turyk et al., 2009;Chao et al., 2010bChao et al., , 2011;;Gascon et al., 2012;Shy et al., 2012).There was a non-significant association of ΣPBDEs with diabetes in three studies (Lim et al., 2008;Turyk et al., 2009;Lee et al., 2011), while Lim et al. (2008) found that BDE-153 shows an inverted U-shaped association with metabolic syndrome.Lee et al. (2012) reports that serum BDE-47 in the elderly is not related to abdominal obesity.However, an earlier report in Taiwan (n = 20) (Wang et al., 2008) (i.e., BDE-47 and 183) and a large-scale study (n = 1367) by Lim et al. (2008) (i.e., BDE-153) both demonstrate a negative correlation between levels of PBDEs and body mass index (BMI).A study for the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) reveals a negative association between serum PBDE levels and child BMI collected from 7-year old Mexican-American children living in an agriculture community in California (n = 272) (Bradman et al., 2012).In addition, two studies, one from Spain (Vizcaino et al., 2010) and one of ours (Shy et al., 2011) have revealed no significant association between maternal education level and cord blood levels of PBDEs.We collected breast milk samples (n = 46) from the same population as the report of Shy et al. (2011) and found that higher breast milk ΣPBDEs are present in older women, those with a higher education level, and those who have had occupational exposure (Chao et al., 2010a).For the CHAMACOS cohort, several factors positively correlate with high levels of PBDEs in 7-year old Mexican-American children, for examples: higher PBDE levels in maternal serum during pregnancy, longer duration of lactation for exclusively breastfed infants, and having no safe places to play in their neighbourhood (Bradman et al., 2012).

PBDEs and Reproduction
Our previous study shows that background breast milk levels of BDE-47, 99, 100, and 209 in 20 mothers possibly had a significant association with low birth weight and small birth length for newborns (Chao et al., 2007).A report from the CHAMACOS study (n = 286, pregnant mothers) states that elevated serum levels of BDE-47, 99, and 100 during pregnancy is related to lower birth weight (Harley et al., 2011).For female reproductive toxicity, increased levels of 99,100,153,and Σ 4 PBDEs in women's serum are related to women spending more time to conceive, but is not associated with changes in the menstrual cycle (Harley et al., 2010).In our previous study, age-adjusted odds ratios (ORs) of 183,207,208,and ΣPBDEs were significantly higher in women with menstrual cycles of average length (i.e., >32 days) compared to the control; while women whose menstruation periods still came irregularly when they were 18 years old had higher ageadjusted ORs of 208,209,and ΣPBDEs than those whose periods came regularly at the same age (Chao et al., 2010b).Prof. Chen and his team members analyzed the National Health and Nutrition Examination Survey's (NHANES) 2003-2004 data to explore associations between female adolescents' exposure to PBDEs and age at menarche to determine if their current serum PBDE levels are linked to menarche occurring at an earlier age in American female adolescents (Chen et al., 2011).With regard to toxicity for male reproduction, Main et al. (2007) found significantly higher ΣPBDEs concentrations in the breast milk of nursing mothers of boys with cryptorchidism than in the nursing mothers of boys not affected by the disorder, and they also found that ΣPBDEs in breast milk associates positively with the serum of luteinizing hormone.Serum BDE-153 in male adults (n = 10) is inversely correlated with semen quality and testes size (Akutsu et al., 2008).In an American study in Massachusetts (Meeker et al., 2009), a study recruited 24 nonsmoking men age 18-54 to investigate house dust PBDE concentrations.Serum hormones revealed that dust PBDE concentrations had negative correlations with the free androgen index, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and positive correlations with inhibin B and sex hormone binding globulin (SHBG).However, epidemiological evidence in PBDEs-induced impacts on reproductive functions remains limited, so it is still unknown whether certain PBDE congeners are able to affect reproduction in males or females.Therefore, longitudinally epidemiological studies to evaluate PBDEs' effects on reproduction are needed.

PBDES AND THYROID HORMONES
Several reports have demonstrated that PBDEs exposure may disrupt thyroid hormone functions, the elimination of thyroid hormones (i.e., thyroxin), bind with thyroid hormone receptors and transporter proteins (i.e., transthyretin), and interfere in-vivo and in-vitro with thyroid homeostasis (Meerts et al., 2000;Legler and Brouwer, 2003;Costa and Giordano, 2007;Yu et al., 2010;Ernest et al., 2012).Many epidemiological studies that evaluate associations of PBDEs exposure and thyroid hormones in adults and newborns have been published previously, but their results are not consistent (Hagmar et al., 2001;Mazdai et al., 2003;Herbstman et al., 2008;Turyk et al., 2008;Dallaire et al., 2009;Kim et al., 2009;Roze et al., 2009;Chevrier et al., 2010;Zhang et al., 2010;Chevrier et al., 2011;Eggesbø et al., 2011;Gascon et al., 2011;Lin et al., 2011).A few studies report the negative impact of cord blood PBDEs on levels of human thyroid hormones after in utero exposure (Herbstman et al., 2008;Lin et al., 2011), but most studies conducted in humans have found no correlations.Recent studies in humans have not consistently concluded that PBDEs exposure disrupts thyroid functions.We listed current reports for associations between human in the early age with exposure to PBDEs and thyroid hormones in Table 2.
Our previous report shows that higher cord blood levels of BDE-153, -154, or -183 are significantly associated with lower cord blood levels of T3 and FT3, whereas increased BDE-100 are positively correlated with a higher T4/T3 ratio (Lin et al., 2011).Similar to the findings of our previous study (Lin et al., 2011), in a cohort study of infants born in the US indicates negative associations between cord blood levels of BDE-100 and BDE-153 and cord blood values of total T4 and FT3 (Herbstman et al., 2008).In contrast, several human studies that assess the associations between PBDEs and thyroid hormones in cord blood find no significant relation ( Mazdai et al., 2003;Kim et al., 2009;Zhang et al., 2010;Chevrier et al., 2011;Gascon et al., 2011;Kim et al., 2011).Specifically, Kim et al. (2009) finds no apparent relationship between fetal T4 and cordblood PBDEs in 108 Korean infants.Zhang et al. (2010) discovers non-significant correlations between PBDEs and levels of total T3 (TT3), TT4, and TSH in 50 cord blood samples from Chinese infants near an electronic waste recycling site in southeast China.Mazdai et al. (2003) finds no apparent correlations between ΣPBDEs and TT4 and FT4 in 12 sample pairs of maternal and cord blood taken from subjects in the United States.A Spanish cohort study also finds that serum PBDEs had no affect on serum levels of TSH, total T3, and FT4 in 4-year-old children (Gascon et al., 2011).A CHAMACOS cohort study shows the negative significant correlation between neonatal TSH and PBDEs in maternal blood during pregnancy and delivery (Chevrier et al., 2011).Kim et al. (2011) discovers no significant associations between thyroid hormones and cord blood PBDEs, but FT4 was negatively and positively correlated with BDE-28 and 153, respectively.Contrary to the above findings, a Dutch study finds that cord blood T3 level have significantly positive correlation with maternal serum levels of BDE-47, BDE-99, and BDE-100 in the 35th week of pregnancy (Roze et al., 2009).Most current epidemiological studies, including our previous study, have not found any relationship between prenatal exposure to PBDEs and cord blood TSH level (Herbstman et al., 2008;Kim et al., 2009;Roze et al., 2009;Zhang et al., 2010;Chevrier et al., 2011;Lin et al., 2011).
In our recently published study (Shy et al., 2012), breast milk levels of certain PBDEs are significantly correlated with cord blood levels of T3, T4, FT4, IGF-1, and FT4/T3, but not TSH.We also find a positive significant association of higher log BDE-154 level with log T4 and log FT4 levels (Shy et al., 2012).An increased log BDE-196 level is significantly and positively linked to the log IGF-1 level.Log FT4 and log IGF-1 has negative significant associations with higher log BDE-99 and log BDE-85 levels, respectively (Shy et al., 2012).A Norwegian Human milk Study (HUMIS) finds no significant association between BDE-47, 99, 153, 154, and 209 in breast milk and TSH in neonates (Eggesbø et al., 2011).In contrast, a higher serum PBDE level is correlated with lower serum TSH values in epidemiological studies in adult men and women, including 270 pregnant American women around their 27th week of gestation (Chevrier et al., 2010), and 308 male Great Lakes sport fish consumers (Turyk et al., 2009), and 110 males consuming Baltic Sea fish (Hagmar et al., 2001).Levels of BDE-28 and 207 in 25 breast milk samples have a significantly positive and negative correlation, respectively, with TSH (Zota et al., 2011).There is still a lack of reliable and consistent epidemiological data to support these findings or to make conjectures based on information extrapolated from in vivo data that PBDEs disrupt thyroid hormone homeostasis (Jugan et al., 2010).
Cord blood FT4 was slightly correlated with increased BDE-99, but weakly correlated with decreased BDE-154.
Although it has been demonstrated that PBDEs exposure delays the neurodevelopment of neonates and adults in animal models, only four epidemiological studies have examined the correlations between infants' or toddlers' neurodevelopment and PBDEs exposure, particularly for octaBDEs, nonaBDEs, and decaBDE (Herbstman et al., 2010;Chao et al., 2011;Shy et al., 2011;Gascon et al., 2012).Two research teams, Herstman et al. (2010) and Gascon et al. (2012), have used the Bayley Scale of Infants and Development, Version II, (BSID-II) to examine whether infants, toddlers, or young children with in utero or postnatal exposure to PBDEs experienced neurodevelopmental disorder.Herbstman et al. (2010) finds that associations are inversely significant for the 12-month Psychomotor Development Index (PDI) (BDE-47), 24-month Mental Development Index (MDI) (BDE-47, 99, and 100), 36-month MDI (BDE-100), 48-month full-scale and verbal IQ (BDE-47, 99, and 100), and 48-month and 72-month performance IQ (BDE-100) when their subjects were prenatally exposed to PBDEs.A recent Spanish study is explored associations between breast milk PBDEs 99,100,153,154,183,and 209) and BSID-II and discovered that only BDE-209 is inversely and significantly correlated with MDI, but this association has only a weak and imprecise margin of significance after adjustments are made for PCBs, HCB, and DDE (Gascon et al., 2012).
In our two previous studies (Chao et al., 2011;Shy et al., 2011), a Bayley-III test (cognition, language, motor, social-emotion, and adaptive behavior) is performed on infants who have been prenatally or perinatal exposed to PBDEs.As compared to the lower PBDEs group (Σ 11 PBDEs < 4.63 ng/g lipid), the higher PBDEs group (Σ 11 PBDEs > 4.63 ng/g lipid) has a significantly higher odds ratio (OR) of the cognition score as well as a lower OR of the adaptive behavior score (Shy et al., 2011).For associations between breast milk PBDEs and neurodevelopment (Chao et al., 2011), a significantly inverse association between BDE-209 and the cognitive scale is found after multivariate stepwise linear regression analyses.In contrast, the language scale is positively correlated with BDE-196 in breast milk.Based on our findings, we suggest that prenatal or perinatal PBDEs exposure may affect infant neurodevelopment.
Two European studies are conducted to examine associations between prenatal PBDEs exposure and children's neuropsychological development and behavior (Roze et al., 2009;Gacon et al., 2011).Roze et al. (2009) states that prenatal PBDE exposure (maternal blood in 35 weeks of gestation) is probably related to irregular outcomes in the field of cognition (the Wechsler Preschool and Primary Scale of Intelligence, Revised Edition (WPPSI-R)) and behavior (the parents completed the Child Behavior Checklist (CBCL)).For instance, negative associations between PBDE exposure and children's neurodevelopment are shown for fine manipulative abilities (BDE-154), verbal memory (BDE-153), and sustained attention (BDE-47, 99, and 100), and positive correlations are found for total behavioral outcome (BDE-99 and 100) and internalizing behavior (BDE-47, 99, and 100) in Dutch children aged 5-6 (Roze et al., 2009).Gacon et al. (2011) reports that prenatal exposure to PBDEs (BDE-47, 99, and 100) and Σ 3 PBDEs (the sum of BDE-47, 99, and 100) are not significantly correlated with cognitive and motor values (McCarthy Scales of Children's Abilities) or social competence (California Preschool Social Competence Scale).Neither of these European studies shows any association with attention deficit hyperactivity disorders (ADHD) in young people who experienced prenatal PBDEs exposure.
In addition, an American report from the Pregnancy Infection and Nutrition (PIN) and PIN Babies (a cohort of North Carolina pregnant women and their children through 36 months of age) assert that breast milk PBDEs are positively linked to externalized behaviors and specifically activity/impulsivity behaviors for toddlers, but their associations are not statistically significant (n = 222) (Hoffman et al., 2012).Toddlers in this PIN cohort study were assessed using the Infant-Toddler Social and Emotional Assessment (ITSEA) test.A new CHAMACOS study has shown an association between prenatal and childhood PBDE exposure and neurodevelopmental problems when the children are 5 (n = 310) and 7 (n = 323) years old (Eskenazi et al., 2013).Prof. Eskenazi and her team examine the relationships between serum PBDEs and children's neurobehavioral development, including attention, motor functioning, and cognition, to show the negative impact of PBDEs in maternal serum transmitted during the perinatal period on Verbal Comprehension IQ when the children reached 7 years old.They also find an inverse association of PBDEs in children's serum with children's Full-Scale IQ and Processing Speed IQ at the age of 7 (Eskenazi et al., 2013).
Consequently, based on the current findings of these eight scientific reports it cannot be firmly concluded whether PBDEs exposure affects neurological development in the early life of human beings or not.The major reasons for the inconclusiveness of the data are probably due to lack of PBDEs exposure data from octa to decaBDE in most reports, and large variations among various evaluation tools.Larger and longitudinal epidemiological studies to examine whether PBDE exposure causes developmental neurotoxicity in infants, toddlers, and children are required.

HBCDs and Human Health
HBCDs are a class of brominated aliphatic cyclic hydrocarbons only used as BFRs.The commercial HBCD mixtures usually contain three stereoisomers, such as α-HBCD, β-HBCD, and γ-HBCD.A global phase-out of HBCDs will be reviewed by the Stockholm Convention POPs in 2013 (Stockholm Convention, 2012).HBCDs are on the Taiwanese Environmental Protection Administration's list of chemicals about which they feel "concerned".In spite of a ban on the use of penta-and octa-BDEs and a voluntary phase out of decaBDE in European and North  -15, 28, 47, 49, 99, 100, 153, 154, 183, 196, 197 8-12th month; Bayley-III m PBDEs in cord blood; higher levels of ΣPBDEs linked to higher cognition and lower adaptive behavior scores Chao et al. (2011) n = 70;ΣPBDEs: 2.92 (median) for the sum of 47,49,99,100,153,154,183,196,197,203,206,207,208,  American countries, HBCDs use is still unrestricted in most industrialized countries, including Taiwan.The widespread use of HBCD isomers in the environment and biota has been reported (Covaci et al., 2006).Few epidemiological studies consider the internal doses of HBCDs and their associated health effects, either in the United States or in Asia, including Taiwan (Aylward and Hays, 2011).Recently, HBCDs exposure has been raised to the level of a global issue of scientific concern due to their persistence and toxicity.The time trend of HBCDs does not show a significant increase or decrease, according to two studies (Asante et al., 2011;Tomes et al., 2012).Breast milk HBCD levels are positively correlated with the number of stereo and video electronics in a home, and are lower in women who regularly choose organic foods compared to those who do not, according to as series of tests performed on Boston mothers (Carignan et al., 2012).Eggesbø et al. (2011) argues that breast milk HBCDs are not related to cord blood TSH.Asante et al. (2011) calculates that the ΣHBCDs daily intake for a breastfed infant through breastfeeding is 0.003 µg/kg b.w./day in Ghana.The daily HBCDs intake for Spanish breastfed infants has been assessed to be 175 ng/kg b.w./day (Eljarrat et al., 2009).Breast milk HBCD levels do not correlate with maternal age and parity in most epidemiological studies (Tanabe and Kunisue, 2007;Malarvannan et al., 2009;Asante et al., 2011;Malarvannan et al., 2012).Human data from numerous biomonitoring studies of HBCDs performed over the past decade reveal that HBCD concentrations in human blood and breast milk are approximately 1 ng/g lipid, and recent risk assessment evaluations from Health Canada and the European Union have identified the levels in those areas as 10 and 20mg/kg day, respectively (Aylward and Hays, 2011).
Currently, a new Belgian study which focuses on BFRs exposure in adolescents examines the associations between exposure levels and secretion of thyroid hormones and neurobehavioral functions, which are determined using the Neurobehavioral Evaluation System (NES-3) (Kiciński et al., 2012).Serum levels of HBCDs are not found to be associated with changes in TSH, FT4, and FT3, and were not consistently correlated with NES-3.In contrast, an average decrease of FT3 is found to be significantly related to BDE-99 or 100, whereas BDE-47 is positively correlated with changes in TSH.Serum ΣPBDE levels are significantly linked to low scores of NES-3.

PBBs and Human Health
At the present time there are very few reports on PBBs in human tissues.A large-scale American epidemiological study for infant-mother pairs with accidental exposure to PBBs from 1975PBBs from to 1997PBBs from (birth cohort in 1975PBBs from -1978PBBs from , first follow-up in 1978PBBs from -1993PBBs from , second follow-up in 1997) ) in Michigan indicates that increased BB-153 in maternal serum has no relation to period of gestation, but has a negative relation to low birth weight (Givens et al., 2007).In another epidemiological study from the same accident cohort (Terrell et al., 2009), the overall proportion of male offspring to the cohort mothers is 0.542, higher than the national male proportion of 0.514.If both parents fit into the PBBs birth cohort, there is an increase in the odds of a male birth with the parents in the high PBBs exposure group as compared to the low exposure group.Small et al. (2011) assert that the mid-range and high PBB (BB-153) in utero exposure increases the odds of spontaneous abortion compared to the lowest exposure group.Time to pregnancy and infertility are not associated with BB-153 in utero exposure.
The comparable PBDD/DF values are reported in Swedish adipose tissue collected in 2007 (Ericson Jogsten et al., 2010).In a Swedish breast milk study (Kotz et al., 2005), 2,3,7,8-TeBDD and 2,3,7,8-TeBDF is detected in breast milk at levels of 0.55 and 0.33 pg/g lipid, respectively.There have been no conclusive studies reporting on the relation of PBDD/DFs exposure with adverse health effects in humans, including infants and toddlers.

CONCLUSIONS
There has been a negative impact on human health, including disruption of thyroid hormone secretion, induction of neurotoxic effects, and changes in neurobehavioral development after humans were exposed to brominated POPs, especially in infants, toddlers, and young children.PBDEs have been recognized as an endocrine disrupting chemical which creates irregularities in the secretions of thyroid hormones and further alters neurological behavior in neonates and adults, according to in in-vivo and epidemiological studies.The results of several animal and epidemiological studies for PBDEs are contradictory based on the current evidence.Recently, many researchers have energetically begun studies on human exposure to HBCDs, but few human studies explore the relation of HBCD exposure with thyroid hormones and neurodevelopment.For PBB and PBDD/DF exposure, few in-vivo and human studies have focused on the correlations of health outcomes.Future work is constantly emerging, and there is significant encouragement for longitudinal studies measuring the effects of human exposure to brominated POPs and their associated effects on health.

Table 1 .
Current concentrations of PBDEs and HBCDs in the indoor environment.

Table 2 .
Current reports for associations between human in the early age with exposure to PBDEs and thyroid hormones.

Table 3 .
Current reports for associations between human in the early age with exposure to PBDEs/HBCDs and neurological behavior.