Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals.

Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause-effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman's reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause-effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.

Toddler behavior, the home environment, and flame retardant exposure.

Toddlers are at increased risk of dust ingestion and subsequently flame retardant (FR) exposure because they often play close to the floor and mouth hands and objects. Exposure to some FRs have been associated to endocrine disruption and neurodevelopmental disorders. Previous research has shown higher FR concentrations in toddlers' serum and urine, but which toddler-behaviors influence exposure levels remains to be determined. We investigated how toddler-behaviors are associated to FRs in hand wipes (HWs) and saliva. Fifty 8-18 month-old children from the Linking EDCs in maternal Nutrition to Child health study, were visited at home. The child's behavior was observed and assessed using a questionnaire. Hand-to-object behavior frequency was associated with HW tris(chloroethyl) phosphate (TCEP), tris(1,3-dichloroisopropyl) phosphate (TDCIPP), tris(phenyl) phosphate, tris(methylphenyl) phosphate, and resorcinol bis(diphenyl phosphate) levels above the detection limit. Children playing with electronics multiple times per week had higher TDCIPP HW levels compared to children playing with electronics once per month or never (p = 0.032 and p = 0.046). Frequent mouth-to-object and frequent mouthing a pacifier were associated with lower TDCIPP (p = 0.019) and tris(2-chloroisopropyl) phosphate (TCIPP) HW levels, respectively (p = 0.002-0.019). Exposure estimates based on hand-to-mouth behavior did not exceed the available reference doses. This is the first study investigating toddler-behavior in relation to FR hand loadings. Although a range of behaviors was investigated, only a few showed a relation with FR HW levels, suggesting that toddler-behavior might not alone be responsible for the elevated FR levels in children. It is therefore important to explore other pathways including dermal absorption and inhalation.

Electronics, interior decoration and cleaning patterns affect flame retardant levels in the dust from Dutch residences.

Consumer products such as furniture foam and electronic device casings are treated with flame retardant chemicals (FRs) to prevent the spread of fire. Many FRs are able to leach out of a product and end up in house dust. FRs in house dust can be taken up by humans through inhalation, ingestion or dermal adsorption. This study aims to identify factors in the home environment that are associated with FR levels in house dust. House dust and a wide range of data on characteristics of electronics, including age and use, interior decoration, domestic house and cleaning patterns, were collected from 50 households in the Netherlands. Decabromodiphenyl ether (BDE209) and several organophosphate flame retardants were measured in dust at detection percentages ranging from 58 to 94%, with median concentrations ranging from 32 ng/g (resorcinol-bis(diphenyl)phosphate (PBDPP)) to 825 ng/g (tris(chloropropyl)phosphate (TCIPP)). For the first time, age, hours of operation and use of the standby function of electronic devices were found to affect FR levels in dust. We found that if the total number of electronic devices purchased before 2008 increased by 1 device, BDE209 levels in house dust significantly increased by 66%. In addition, house dust from homes with carpeted floors was significantly associated with a 70-80% lower concentration of several FRs compared to homes with smooth floors (e.g., laminate). Less frequent vacuum cleaning and dusting were significantly associated with 41 to 88% higher concentrations of several FRs in dust. These associations suggest that actions such as frequent vacuum cleaning and dusting as well as different FR regulations for electronic devices affect indoor exposure levels.

Prenatal exposure to endocrine disrupting chemicals and risk of being born small for gestational age: Pooled analysis of seven European birth cohorts.

BACKGROUND AND AIMS: There is evidence that endocrine disrupting chemicals (EDCs) have developmental effects at environmental concentrations. We investigated whether some EDCs are associated with the adverse birth outcome Small for Gestational Age (SGA). METHODS: We used PCB 153, p,p'-DDE, HCB, PFOS and PFOA measured in maternal, cord blood or breast milk samples of 5446 mother-child pairs (subset of 693 for the perfluorinated compounds) from seven European birth cohorts (1997-2012). SGA infants were those with birth weight below the 10th percentile for the norms defined by gestational age, country and infant's sex. We modelled the association between measured or estimated cord serum EDC concentrations and SGA using multiple logistic regression analyses. We explored effect modification by child's sex and maternal smoking during pregnancy. RESULTS: Among the 5446 newborns, 570 (10.5%) were SGA. An interquartile range (IQR) increase in PCB 153 was associated with a modestly increased risk of SGA (odds ratio (OR) of 1.05 [95% CI: 1.04-1.07]) that was stronger in girls (OR of 1.09 [95% CI: 1.04-1.14]) than in boys (OR of 1.03 [95% CI: 1.03-1.04]) (p-interaction = 0.025). For HCB, we found a modestly increased odds of SGA in girls (OR of 1.04 [95% CI: 1.01-1.07] per IQR increase), and an inverse association in boys (OR of 0.90 [95% CI: 0.85-0.95]) (p-interaction = 0.0003). Assessment of the HCB-sex-smoking interaction suggested that the increased odds of SGA associated with HCB exposure was only in girls of smoking mothers (OR of 1.18 [95% CI: 1.11-1.25]) (p-interaction = 0.055). Higher concentrations of PFOA were associated with greater risk of SGA (OR of 1.64 [95% CI: 0.97-2.76]). Elevated PFOS levels were associated with increased odds of SGA in newborns of mothers who smoked during pregnancy (OR of 1.63 [95% CI: 1.02-2.59]), while an inverse association was found in those of non-smoking mothers (OR of 0.66 [95% CI: 0.61-0.72]) (p-interaction = 0.0004). No significant associations were found for p,p'-DDE. CONCLUSIONS: Prenatal environmental exposure to organochlorine and perfluorinated compounds with endocrine disrupting properties may contribute to the prevalence of SGA. We found indication of effect modification by child's sex and smoking during pregnancy. The direction of the associations differed by chemical and these effect modifiers, suggesting diverse mechanisms of action and biological pathways.

Legacy and alternative halogenated flame retardants in human milk in Europe: Implications for children's health.

In this study, 10 polybrominated diphenyl ethers (PBDEs) and 19 alternative halogenated flame retardants (AFRs) were determined in >450 human milk samples across three European countries, representing northern, western and eastern Europe. This study provides first insights into the occurrence of selected AFRs in mother milk samples and compares them among three European countries. Sums of median concentrations of the most frequently detected PBDEs were 2.16, 0.88 and 0.45ngg-1 lipid weight (lw) in Norway, the Netherlands and Slovakia, respectively. The sum of the concentrations of AFRs ranged from 0.14 to 0.25ngg-1lw in all countries, which was 2 to 15 times less compared to Σ7PBDEs. The Penta-BDE replacement, bis(2-ethylhexyl) tetrabromophthalate, BEH-TEBP, was present at the greatest concentrations of any of the AFRs and in some samples exceeded concentrations of BDE 47 and BDE 153. Four AFRs including bromobenzenes (hexabromobenzene, pentabromobenzene, pentabromotoluene) and another Penta-BDE replacement (2-ethylhexyl-2,3,4,5-tetrabromobenzoate, EH-TBB) were detected in >42% of all human milk samples. Because of the potential developmental neurotoxicity of the halogenated flame retardants, infant dietary intakes via breastfeeding were estimated; in four cases the intakes of BDE 47 exceeded the reference dose indicating that the present concentrations may pose a risk for children.

Toddler exposure to flame retardant chemicals: Magnitude, health concern and potential risk- or protective factors of exposure: Observational studies summarized in a systematic review.

Endocrine disrupting flame retardant (FR) chemicals form a human health concern, that is investigated mostly from the perspective of adult- and early life exposure. No overview of studies on toddler exposure and health effects exist. However, toddlerhood is a critical developmental period and toddlers are at increased risk for exposure because of their age-specific behavior. This systematic review encompasses toddler FR exposure studies in three countries, associated health effects and potential environmental, demographic, or behavioral risk- or protective factors for toddler exposure. A systematic literature search in four databases (PubMed, Embase.com, The Cochrane Library (via Wiley) and Web of Science Core collection) resulted in the identification of ten publications representing seven unique studies that measured brominated and/or phosphorylated FRs in toddlers' (8-24 month-old) serum, urine, hand wipes and feces. This review showed that toddlers are exposed to a range of FRs, that thyroid hormone disruption is associated with FR exposure and that factors in the indoor environment, including products such as plastic toys, might increase FR exposure. Considering the limited amount of studies, and the variety of biological matrices, FRs, and risk- and protective factors, this review did not reveal a uniform pattern of toddler exposure across the different cohorts studied. More evidence is necessary and considering the feasibility of invasive sampling in young children, we suggest to emphasize research on non-invasive matrices.

Thyroid-stimulating hormone levels in newborns and early life exposure to endocrine-disrupting chemicals: analysis of three European mother-child cohorts.

BackgroundVarious studies have reported interactions between thyroid hormones and early life chemical exposure. Our objective was to analyze the associations between markers of endocrine-disrupting chemical exposure and thyroid function in newborns, determined through heel prick blood spots.MethodsThree European mother-child cohorts (FLEHSI-Belgium, HUMIS-Norway, and the PCB cohort-Slovakia. Total n=1,784) were pooled for the purpose of this study. Data on thyroid-stimulating hormone (TSH) were obtained from national neonatal screening registries, and samples of cord plasma and/or breast milk were collected to determine exposure to various chemicals. Multiple regression models were composed with exposure and cohort as fixed factors, and adjustments were made for a priori defined covariates.ResultsMedian TSH concentrations were 1, 1.10, and 2.76 mU/l for the Belgian, Norwegian, and Slovak cohorts, respectively. For polychlorinated biphenyl (PCB)-153 and dichlorodiphenyldichloroethylene (p,p'-DDE), children in the third exposure quartile had a 12-15% lower TSH at birth. Results remained unchanged after additional adjustment for birth weight and gestational weight gain. No effect on TSH was observed for the other compounds.ConclusionEarly life exposure to PCB-153 and p,p'-DDE impacts newborn TSH levels. Higher exposure levels were associated with 12-15% lower TSH levels.

An effective clean-up technique for GC/EI-HRMS determination of developmental neurotoxicants in human breast milk.

The increasing number of children suffering from developmental disorders has raised questions regarding their association with the presence of environmental contaminants in mothers and children. We therefore developed a new method for the determination of 78 proven and potential developmental neurotoxicants, including polychlorinated biphenyls, legacy pesticides, pyrethroids, and old and new halogenated flame retardants in breast milk. The essential part of sample preparation was dialysis as a non-destructive clean-up step which was newly used at 10 °C and showed more efficient lipid removal (up to 96%) than the conventional methods such as gel permeation chromatography or freezing-lipid filtration and thus ensured low limits of detection (LOD) by reducing the sample volume prior to injection. Next advantages were significant solvent reduction and no risk of sample cross-contamination. Gas chromatography coupled with high resolution mass spectrometry (GC-HRMS) was subsequently used for the separation and compound quantification. The method was validated using breast milk samples fortified with the analyzed compounds. Recoveries for most of the compounds ranged from 63 to 121% with a relative standard deviation of 2-25%, and LODs ranged between 0.001 and 0.87 ng g-1 lipid weight. The method was applied to breast milk samples from a Dutch birth cohort where 35 out of the 78 compounds were quantified in more than 60% of the samples. For novel flame retardants, the method provides unique results regarding their occurrence in human matrices in Europe. Overall, the analysis of a complex mixture of developmental neurotoxicants could be useful for the assessment of the influence of the studied compounds to child health and development. Graphical abstract Flow diagram of the method and levels of the developmental neurotoxicants in Dutch human milk samples.

Developmental neurotoxicants in human milk: Comparison of levels and intakes in three European countries.

Developmental neurotoxicants (DNTs), such as methylmercury (MeHg), polychlorinated biphenyls (PCBs) and selected organochlorine pesticides (OCPs), have gained increasing interest recently due to their possible relation to developmental disorders in children, which are increasing worldwide. We analyzed levels of 14 developmental neurotoxicants in human milk samples from Slovakia (n=37), the Netherlands (n=120) and Norway (n=388). Positive identification for most target analytes was >95% in all samples. In all three countries MeHg was measured for the first time in mother milk. The highest MeHg levels were observed in Norway (39pgg-1 ww) with the highest fish consumption. Levels of indicator PCBs (iPCBs, sum of PCB 28, 52, 101, 138, 153 and 180), HCB and DDE+DDT were 2-4 times higher in Slovakia compared to the Netherlands or Norway. The levels of MeHg and organochlorine compounds were used for calculations of weekly or daily intakes (top-down approach) by means of pharmacokinetic modeling. The intakes ranged from 0.014 to 0.142µgkgbw-1week-1 for MeHg and from 0.043 to 17.4ngkgbw-1day-1 for organochlorine compounds in all three countries. Intakes of iPCBs exceeded a tolerable daily intake of 10ngkgbw-1day-1 in 16% of the Slovak participants. The top-down estimates were compared with bottom-up intakes based on national dietary estimates and the results showed good consistency between both approaches, with the bottom-up intakes exceeding the top-down by a factor of maximum 3.8 for iPCBs in the Netherlands and 3.9 for HCB in Slovakia. This confirms that food consumption in all three countries represents the dominant pathway of exposure to these developmental neurotoxicants.

Prenatal Exposure to Perfluoroalkyl Substances and Behavioral Development in Children.

BACKGROUND: In recent years, prevalence rates of behavioral disorders in children have increased. One factor possibly implied in the etiology of behavioral disorders is exposure to perfluoroalkyl substances (PFASs). The use of PFASs is highly integrated into everyday life, and exposure is ubiquitous. Exposure to PFASs during early life may be particularly harmful, as it represents a critical time window for brain development. However, research in the area is limited, especially among preschool children. The objective of the current study was to explore the relationship between prenatal exposure to several PFASs and behavioral development at the age of 18 months. METHODS: Data from the Dutch cohort LINC (Linking Maternal Nutrition to Child Health) were used. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord plasma. The total exposure of PFASs was also calculated (ΣPFASs). Behavioral development was assessed with the Child Behavior Checklist 1.5-5 (CBCL 1.5-5). The CBCL scales "Attention Deficit Hyperactivity Disorder" (ADHD) and "Externalizing problems" were used for further analysis. Separate regression models were composed for each combination, in which exposure levels were classified in tertiles. Both whole population and sex-stratified analyses were performed. A family history of ADHD, the educational level, smoking or using alcohol or illicit drugs during pregnancy were considered as confounders. In total, data from 76 mother-child pairs was included. RESULTS: No significant associations were found between prenatal PFAS exposure and ADHD scores in the whole population and in the sex-stratified analyses. With regard to externalizing behavior, a significant negative association was found between the highest levels of ΣPFAS exposure and externalizing problem behavior in the whole population, but only in the crude model. After stratifying for sex, boys in the second and third tertile of exposure to PFOA presented significantly lower scores on the Externalizing Problem Scale than boys with the lowest exposure levels in the adjusted model. Girls exposed to higher levels of ΣPFAS exposure (T2) showed significantly lower scores on the Externalizing Problem Scale, in both crude and adjusted models. No significant associations with PFOS were found. CONCLUSIONS: RESULTS from the current study show that prenatal exposure to PFOA was negatively related to externalizing behavior in boys. RESULTS were different for boys and girls, emphasizing that mechanisms at work might be sex-dependent. However, results should be interpreted with caution as the sample size was small.

LInking EDCs in maternal Nutrition to Child health (LINC study) - protocol for prospective cohort to study early life exposure to environmental chemicals and child health.

BACKGROUND: The presence of chemicals in the environment is ubiquitous. Human biomonitoring studies have shown that various chemicals can be detected in the majority of the population, including pregnant women. These compounds may pass the placenta, and reach the fetus. This early life exposure in particular may be detrimental as some chemicals may disrupt the endocrine system, which is involved in various processes during development. The LINC study is a prospective birth cohort designed to study associations between early life environmental exposures and child health, including growth and neurodevelopment. The purpose of this paper is to give an overview of this cohort. METHODS AND DESIGN: Recruitment for this cohort has started in 2011 in three Dutch areas and is still ongoing. To date over 300 mother-child pairs have been included. Women are preferably included during the first trimester of pregnancy. Major congenital anomalies and twin births are reasons for exclusion. To assess exposure to environmental chemicals, cord blood, placenta, meconium and vernix are collected. Parents collect urine of the child shortly after birth and breast milk in the second month of life. Exposure to a broad range of environmental chemicals are determined in cord plasma and breast milk. Furthermore various hormones, including leptin and cortisone, are determined in cord plasma, and in heel prick blood spots (thyroxine). Data on anthropometry of the child is collected through midwives and youth health care centres on various time points until the child is 18 months of age. Furthermore cognitive development is monitored by means of the van Wiechen scheme, and information on behavioral development is collected by means of the infant behavior questionnaire and the child behavior checklist. When the child is 12 months of age, a house visit is scheduled to assess various housing characteristics, as well as hand-to-mouth behavior of the child. At this visit exposure of the child to flame retardants (with endocrine disrupting properties) in house dust is determined by means of body wipes. They are furthermore also measured in a saliva sample of the child. Next to these measurements, women receive questionnaires each trimester regarding amongst others lifestyle of the parents, general health of the parents and the child, and mental state of the mother. DISCUSSION: This study was approved by the medical ethics committee of the VU University Medical Centre. Consent for the infant is given by the mother, who is specifically required to give consent for both herself as well as her child. Results will be published regardless of the findings of this study, and will be widely disseminated among related medical stakeholders (e.g. midwives and pediatricians), policy makers, and the general public.

Prenatal exposure to endocrine disrupting chemicals and birth weight-A prospective cohort study.

Prenatal exposure to endocrine disrupting chemicals may affect fetal development through disruption of hormonal actions and epigenetic modifications, potentially predisposing individuals to later on-set health risks, such as obesity. The objective of this study was to determine associations between biological exposure markers of various endocrine disrupting chemicals and birth weight in a newly established, prospective mother-child cohort in the Netherlands. Birth weight (n = 91) was obtained from birth records, and exposure to dichlorodiphenyldichloroethylene (DDE), three di-2-ethylhexyl phthalate (DEHP) metabolites, polychlorinated biphenyl-153, perfluorooctanesulfonic acid (PFOS), and perfluorooctanoic acid (PFOA) was determined in cord plasma. For DDE, exposure was also measured in breast milk. Linear regression analysis was used to determine associations between compounds and birth weight, which were stratified for gender and adjusted for a priori defined covariates. Increased exposure to DDE was associated with lower birth weight in boys (>95.89 ng L-1, -325.9 g, 95% CI -634.26 to -17.56), whereas in girls a tendency towards a higher birth weight was observed. Lower birth weights for boys were also observed for high exposure to MECPP, and to a certain extent also for PFOA. MEHHP and PFOS exposure on the other hand were associated with higher birth weights in boys. In girls no effects were observed for these compounds. It can be concluded that prenatal exposure to DDE, perfluorinated alkyl acids, and phthalates was associated with changes in birth weight in this population. Associations were gender specific, and appeared to be non-linear. Since the population was relatively small, results should be interpreted with caution.

Prenatal exposure to endocrine disrupting chemicals in relation to thyroid hormone levels in infants - a Dutch prospective cohort study.

BACKGROUND: Endocrine disrupting chemicals (EDCs) present in the environment may disrupt thyroid hormones, which in early life are essential for brain development. Observational studies regarding this topic are still limited, however as the presence of chemicals in the environment is ubiquitous, further research is warranted. The objective of the current study was to assess the association between exposure markers of various EDCs and thyroxine (T4) levels in newborns in a mother-child cohort in the Netherlands. METHODS: Exposure to dichlorodiphenyldichloroethylene (DDE), three di-2-ethylhexyl phthalate (DEHP) metabolites, hexachlorobenzene (HCB), polychlorinated biphenyl (PCB)-153, perfluorooctanesulfonic acid (PFOS), and perfluorooctanoic acid (PFOA) was determined in cord plasma or breast milk, and information on T4 levels in heel prick blood spots was obtained through the neonatal screening programme in the Netherlands. Linear regression models were composed to determine associations between each of the compounds and T4, which were stratified for gender and adjusted for a priori defined covariates. RESULTS: Mean T4 level was 86.9 nmol/L (n = 83). Girls in the highest quartile of DDE and PFOA exposure showed an increased T4 level compared to the lowest quartile with both crude and fully adjusted models (DDE > 107.50 ng/L, +24.8 nmol/L, 95% CI 0.79, 48.75; PFOA > 1200 ng/L, +38.6 nmol/L, 95% CI 13.34, 63.83). In boys a lower T4 level was seen in the second quartile of exposure for both PFOS and PFOA, however after fully adjusting the models these associations were attenuated. No effects were observed for the other compounds. CONCLUSION: DDE and perfluorinated alkyl acids may be associated with T4 in a sex-specific manner. These results should however be interpreted with caution, due to the relatively small study population. More research is warranted, as studies on the role of environmental contaminants in this area are still limited.

First year growth in relation to prenatal exposure to endocrine disruptors - a Dutch prospective cohort study.

Growth in the first year of life may already be predictive of obesity later in childhood. The objective was to assess the association between prenatal exposure to various endocrine disrupting chemicals (EDCs) and child growth during the first year. Dichloro-diphenyldichloroethylene (DDE), mono(2-ethyl-5-carboxypentyl)phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP), mono(2-ethyl-5-oxohexyl)phthalate (MEOHP), polychlorinated biphenyl-153, perfluorooctanesulfonic acid, and perfluoro-octanoic acid were measured in cord plasma or breast milk. Data on weight, length, and head circumference (HC) until 11 months after birth was obtained from 89 mother-child pairs. Mixed models were composed for each health outcome and exposure in quartiles. For MEOHP, boys in quartile 1 had a higher BMI than higher exposed boys (p = 0.029). High DDE exposure was associated with low BMI over time in boys (0.8 kg/m2 difference at 11 m). Boys with high MECPP exposure had a greater HC (1.0 cm difference at 11 m) than other boys (p = 0.047), as did girls in the second quartile of MEHHP (p = 0.018) and DDE (p < 0.001) exposure. In conclusion, exposure to phthalates and DDE was associated with BMI as well as with HC during the first year after birth. These results should be interpreted with caution though, due to the limited sample size.

Obesogenic effects of endocrine disruptors, what do we know from animal and human studies?

BACKGROUND: Hormonal actions and activation of receptors involved in adipogenesis and brain development during the prenatal period may be affected by exposure to certain chemicals. Experimental studies have shown that amongst others polychlorinated biphenyl (PCB)-153 and dichlorodiphenyltrichloroethane (DDT) may have obesogenic effects in prenatally exposed mice. OBJECTIVE: To provide an overview of five classes of chemicals which have frequently been indicated as potential obesogens, and to discuss the evidence available regarding early life exposure to these compounds and overweight later in life. METHODS: Pubmed was systematically searched for publications which related early life exposure to endocrine disrupting chemicals (EDCs) to growth parameters later in life. We included 19 studies, which were published from 1995 and onwards. RESULTS: Both positive and negative associations are observed between early life exposure and weight or height at various ages, including as early as 14 months, as well as until 20 years of age. In none of the included studies negative associations between perinatal exposure to EDCs and body mass index (BMI) were found and in several studies a positive association was observed. Dose-response relations appear to be non-monotonic. CONCLUSION: For certain EDCs, early life exposure may be associated with weight homeostasis later in life, however not necessarily in an obesogenic direction. More sensitive measures of adiposity as well as long-term follow-up are warranted for future studies.

Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review.

AIM: To provide an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. METHODS: A review of the literature (PubMed) was performed. Exposure-related keywords, including various chemicals, were matched with keywords describing outcome. Animal studies as well as publications not written in English were excluded. In total, 834 titles were retrieved. The final selection included 21 publications. RESULTS: Positive associations were found for ASD in relation to exposure to all chemicals investigated, which included hazardous air pollutants, pesticides and bisphenol A (BPA). Increased risks of ADHD or positive associations were found for exposure to polychlorinated biphenyls (PCBs), dialkyl phosphate (DAP) and chlorpyrifos. BPA, polybrominated diphenylethers (PBDEs) and low molecular weight (LMW) phthalates were positively associated with externalizing behaviour. Five of 17 studies did not find any association between exposure and ADHD. CONCLUSION: Perinatal exposure to EDCs appears to be associated with the occurrence of ASD as well as ADHD. Disruption of thyroid hormone function and gamma-aminobutyric acid (GABA)ergic mechanisms may offer an explanation for the observed relations; though, conclusive evidence in humans is limited.