The Joint Effect of Perceived Psychosocial Stress and Phthalate Exposure on Hormonal Concentrations during the Early Stage of Pregnancy: A Cross-Sectional Study.

Phthalates alter the hormonal balance in humans during pregnancy, potentially affecting embryonic and fetal development. We studied the joint effect of exposure to phthalates, quantified by urinary phthalate metabolite concentration, and perceived psychological stress on the concentration of hormones in pregnant women (n = 90) from the Nitra region, Slovakia, up to the 15th week of pregnancy. We used high-performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS), and electro-chemiluminescence immunoassay to determine urinary concentrations of phthalates and serum concentrations of hormones, respectively. We used Cohen perceived stress scale (PSS) to evaluate the human perception of stressful situations. Our results showed that mono(carboxy-methyl-heptyl) phthalate (cx-MiNP) and a molar sum of di-iso-nonyl phthalate metabolites (ΣDiNP) were negatively associated with luteinizing hormone (LH) (p ≤ 0.05). Mono(hydroxy-methyl-octyl) phthalate (OH-MiNP) and the molar sum of high-molecular-weight phthalate metabolites (ΣHMWP) were positively associated with estradiol (p ≤ 0.05). PSS score was not significantly associated with hormonal concentrations. When the interaction effects of PSS score and monoethyl phthalate (MEP), cx-MiNP, ΣDiNP, and ΣHMWP on LH were analyzed, the associations were positive (p ≤ 0.05). Our cross-sectional study highlights that joint psychosocial stress and xenobiotic-induced stress caused by phthalates are associated with modulated concentrations of reproductive hormones in pregnant women.

Gene expression signatures in PCB-exposed Slovak children in relation to their environmental exposures and socio-physical characteristics.

Our previous gene expression studies in a PCB-exposed cohort of young children in Slovakia revealed that early-life exposures to PCBs and other organochlorine compounds were associated with significant alterations across several pathogenetic pathways. The present study was undertaken to further explore the high-throughput qRT-PCR-based gene expression effects by using TaqMan low-density array (TLDA) for selected genes in a sample of 55 children from the cohort. We analyzed the transcriptional changes of 11 genes in relation to PCB and organochlorine pesticide exposure levels (including DDT, DDE, HCH, and HCB), and to BMI and ethnicity in this cohort. The results indicated an overall downregulation of expression of these genes. Maximum downregulation (in fold change) was observed in the ENTPD3 gene, and the minimum level of downregulation was in CYP2D6. As per our multinomial regression model study, downregulation of LEPR gene was significantly directly correlated with all the exposure variables. Downregulation of APC, ARNT, CYP2D6, LEPR, LRP12, and MYC genes was directly correlated with BMI (kg/m2) of the individuals. Gender-specific differences in gene expression were observed in CYP2D6 (p-value 0.0001) and LEPR (p-value 0.028), while downregulation of CYP2D6 (p-value 0.01), LEPR (p-value 0.02), LRP12 (p-value 0.04), and MYC (p-value 0.02) genes was consistently observed in Roma children compared to Caucasians. The investigation of such health disparities must be emphasized in future research, together with interventions to reduce the health consequences of PCB exposures. In this context, we emphasize the importance of biomarker-based approaches to future research on genetic susceptibility to the effects of these compounds.

Risk of Abdominal Obesity Associated with Phthalate Exposure of Nurses.

Background: Occupational health hazards associated with phthalate exposure among nurses are still not well understood. Methods: We used high-performance liquid chromatography and tandem mass spectrometry to analyze phthalates. Anthropometric measurements and questionnaires were conducted. Results: We observed associations between mono-benzyl phthalate (MBzP) and body mass index (BMI), hip circumference (HC), waist circumference (WC), waist to height ratio (WHtR), and fat mass index (FMI), visceral fat content, BMI risk and hip index risk (HIrisk), adjusted to consumer behavior and consumer practices (r = 0.36−0.61; p ≤ 0.046). In the same model, we detected an association between mono-n-butyl phthalate (MnBP) and waist to hip ratio (WHR; r = 0.36; p = 0.046), mono-carboxy-isononyl phthalate (cx-MiNP) and BMI (r = 0.37; p = 0.043), HC (r = 0.4; p = 0.026) and WHtR (r = 0.38; p = 0.037), between mono-oxo-isononyl phthalate oxo (MiNP) and HC (r = 0.36; p = 0.045), mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (oxo-MEHP) and HIrisk (r = 0.38−0.41; p ≤ 0.036), between oxo-MEHP and Anthropometric Risk Index (ARI risk; r = 0.4; p = 0.028). We detected a relationship between BMI and MBzP (ß = 0.655; p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; ß = −0.365; p = 0.003), between hip circumference and MBzP (ß = 0.486; p < 0.001), MEHP (ß = −0.402; p = 0.001), and sum of secondary metabolites of diisononyl phthalate (∑DiNP; ß = 0.307; p = 0.016). We observed a relationship between fat content and MBzP (ß = 0.302; p = 0.033), OH-MnBP (ß = −0.736; p = 0.006) and MiBP (ß = 0.547; p = 0.046), visceral fat content and MBzP (ß = 0.307; p = 0.030), HI-risk and MBzP (ß = 0.444; p = 0.001), ARI-risk and sum of di-n-butyl phthalate metabolites (∑DnBP; ß = 0.337; p = 0.018). We observed an association between the use of protective equipment with cx-MiNP. Conclusions: Occupational exposure to phthalates may induce abdominal obesity and result in obesity-related metabolic disorders.

Application of a pharmacokinetic model in characterizing sources of polychlorinated biphenyl exposure and determining threshold daily intakes for adverse health effects in infants and toddlers.

Characterization of PCB exposure sources for vulnerable population groups is essential to minimize the health effects of PCB exposure. At the same time, it is important to consolidate the knowledge on threshold intakes of PCBs for infants and toddlers to prevent health effects. We estimated total PCB concentrations from birth to 2 years of age in children from Slovak and Czech populations, which continue to have high PCB concentrations in breast milk. Using a pharmacokinetic (PK) model, we characterized dominant PCB exposure sources and estimated new threshold estimated daily intakes (TEDI) (above which adverse effects cannot be excluded) for postnatal PCB exposure in infants and toddlers. In the PK model, concentrations of seven indicator PCBs in breast milk and cord blood samples from 291 mother-child pairs from the Slovak birth cohort, and 396 breast milk samples from Czech mothers we used, together with their physiological characteristics and PCB concentrations from other exposure sources (food, dust, air). The estimated total PCB concentrations in children's blood at different ages were compared with threshold PCB concentrations of 500, 700 and 1000 ng·glipid-1 in serum proposed by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) and the German Environment Agency (UBA), above which possible adverse health effects may be expected. We estimated that up to 20.6% of Slovak children and up to 45.7% of Czech children at two years of age exceeded the threshold value of 700 ng·glipid-1 in blood. Mean TEDIs leading to values of 500 ng·glipid-1 in blood for children up to two years ranged between 110 and 220 ng·kg-1·bw·day-1, varying according to breastfeeding duration. Breast milk and prenatal exposure contributed to 71%-85% of PCBs exposure at two years of age. In contrast, the contributions of PCBs from dust and indoor air were negligible.

Pre- and postnatal polychlorinated biphenyl exposure and cognitive and behavioral development at age 45 Months in a cohort of Slovak children.

Evidence of associations of pre- and postnatal exposure to polychlorinated biphenyls (PCBs) with cognitive development beyond early childhood is inconsistent. A previous report from this cohort observed adverse associations between early life PCB exposures and infant Bayley scores at age 16 months. The present study examines pre- and postnatal PCB exposures in relation to both behavior and cognitive development at age 45 months. Participants were 472 mother-child pairs residing in an area of eastern Slovakia characterized by environmental contamination with PCBs, which resulted in elevated blood serum concentrations. PCB-153 and PCB-118 concentrations were measured in maternal and in infant 6-, 16-, and 45-month serum samples. At age 45 months, children were administered five subtests of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), and mothers completed the Child Behavior Checklist (CBCL). Negative binomial and multiple linear regressions were used to estimate PCB-CBCL and PCB-WPPSI-III subtest score associations, respectively. Pre- and postnatal levels of PCB-153 and PCB-118 were not associated with cognitive performance on the WPPSI-III in this cohort. There was some suggestion that higher postnatal PCB concentrations were associated with more sleep problems and feelings of depression and anxiousness.

Targeted and suspect screening of plasticizers in house dust to assess cumulative human exposure risk.

Indoor dust is an important exposure route to anthropogenic chemicals used in consumer products. Plasticizers are common product additives and can easily leach out of the product and partition to dust. Investigations of plasticizers typically focus on a subset of phthalate esters (PEs), but there are many more PEs in use, and alternative plasticizers (APs) are seeing greater use after recognition of adverse health effects of PEs. In this study we use full scan high resolution mass spectrometry for targeted and suspect screening of PEs and APs in house dust and to assess the potential risk of human exposure. House dust samples from Eastern Slovakia were investigated and concentrations of ∑12PEs and ∑5APs ranged 12-2765 µg/g and 45-13,260 µg/g, respectively. APs were at similar levels to PEs, indicating common usage of these compounds in products in homes. Evaluation of individual compound toxicity combined with human intake via dust ingestion suggested PEs are of lower priority compared to semivolatile organic compounds such as polychlorinated biphenyls due to their lower toxicity. However, cumulative risk assessment (CRA) is a more appropriate evaluation of risk, considering the presences of many PEs in dust and their similar toxic mode of action. CRA based on median toxicity reference values (TRVs) suggested acceptable risks for dust ingestion, however, the wide range of literature-derived TRVs is a large uncertainty, especially for the APs. Use of newer TRVs suggest risk from dust ingestion alone, i.e. not even considering diet, inhalation, and dermal contact. Additionally, screening of full-scan instrumental spectra identified a further 40 suspect PE compounds, suggesting the CRA based on the 12 target PEs underestimates the risk.

Biomarkers of metabolic disorders and neurobehavioral diseases in a PCB- exposed population: What we learned and the implications for future research.

Polychlorinated biphenyls (PCBs) are one of the original twelve classes of toxic chemicals covered by the Stockholm Convention on Persistent Organic Pollutants (POP), an international environmental treaty signed in 2001. PCBs are present in the environment as mixtures of multiple isomers at different degree of chlorination. These compounds are manmade and possess useful industrial properties including extreme longevity under harsh conditions, heat absorbance, and the ability to form an oily liquid at room temperature that is useful for electrical utilities and in other industrial applications. They have been widely used for a wide range of industrial purposes over the decades. Despite a ban in production in 1979 in the US and many other countries, they remain persistent and ubiquitous in environment as contaminants due to their improper disposal. Humans, independent of where they live, are therefore exposed to PCBs, which are routinely found in random surveys of human and animal tissues. The prolonged exposures to PCBs have been associated with the development of different diseases and disorders, and they are classified as endocrine disruptors. Due to its ability to interact with thyroid hormone, metabolism and function, they are thought to be implicated in the global rise of obesity diabetes, and their potential toxicity for neurodevelopment and disorders, an example of gene by environmental interaction (GxE). The current review is primarily intended to summarize the evidence for the association of PCB exposures with increased risks for metabolic dysfunctions and neurobehavioral disorders. In particular, we present evidence of gene expression alterations in PCB-exposed populations to construct the underlying pathways that may lead to those diseases and disorders in course of life. We conclude the review with future perspectives on biomarker-based research to identify susceptible individuals and populations.

Occupational Hazards and Risks Associated with Phthalates among Slovakian Firefighters.

Despite increasing attention to the occupational risk of firefighters, little is known about phthalate exposure. In our study, we detected mono-isobutyl phthalate (MiBP), mono-n-buthyl phthalate (MnBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MECPP), and mono(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP) in each urine sample. We detected positive association between MnBP, MiBP, mono-2-ethylhexyl phthalate (MEHP), 5OH-MEHP, 5oxo-MEHP, 5cx-MECPP, mono-isononyl phthalate (MiNP), the sum of low (∑LMWP) and high molecular-weight phthalates (∑HMWP). and Tiffeneau-Pinelli index (the ratio of forced expiratory volume in 1/ forced vital capacity; FEV1/FVC; p = 0.001-0.04) and the percent predicted value (%PV) of FEV1/FVC (p = 0.005-0.05) and negative association between MiNP and peak expiratory flow (PEF; r = -0.31; p = 0.084). We observed a positive association between phthalate metabolites (MnBP, 5OH-MEHP, 5oxo-MEHP, 5cx-MECPP, 2cx-MMHP, ∑LMWP, and ∑HMWP) and waist-to-hip ratio (WHR; p = 0.003-0.09) and body shape index (ABSI; p = 0.039-0.09) and a negative association between MnBP, ∑LMWP, and hip circumference (p = 0.005-0.02). We detected association between concentrations of 5OH-MEHP, 5cx-MECPP, 5oxo-MEHP, and MnBP and consumption of food heating in plastic material in microwave (p = 0.02-0.04) and between probands who ate margarines and vegetable fat packed in plastic containers and concentration of MMP (p = 0.03). Results of multivariate regression indicated that exposure to phthalates could be linked with changing body structure, which subsequently affects values of pulmonary functions in firefighters.

Linking past uses of legacy SVOCs with today's indoor levels and human exposure.

Semivolatile organic compounds (SVOCs) emitted from consumer products, building materials, and indoor and outdoor activities can be highly persistent in indoor environments. Human exposure to and environmental contamination with polychlorinated biphenyls (PCBs) was previously reported in a region near a former PCB production facility in Slovakia. However, we found that the indoor residential PCB levels did not correlate with the distance from the facility. Rather, indoor levels in this region and those reported in the literature were related to the historic PCB use on a national scale and the inferred presence of primary sources of PCBs in the homes. Other SVOCs had levels linked with either the activities in the home, e.g., polycyclic aromatic hydrocarbons (PAHs) with wood heating; or outdoor activities, e.g., organochlorine pesticides (OCPs) with agricultural land use and building age. We propose a classification framework to prioritize SVOCs for monitoring in indoor environments and to evaluate risks from indoor SVOC exposures. Application of this framework to 88 measured SVOCs identified several PCB congeners (CB-11, -28, -52), hexachlorobenzene (HCB), benzo(a)pyrene, and γ-HCH as priority compounds based on high exposure and toxicity assessed by means of toxicity reference values (TRVs). Application of the framework to many emerging compounds such as novel flame retardants was not possible because of either no or outdated TRVs. Concurrent identification of seven SVOC groups in indoor environments provided information on their comparative levels and distributions, their sources, and informed our assessment of associated risks.

Environmental ototoxicants, a potential new class of chemical stressors.

Hearing loss is an injury that can develop over time, and people may not even be aware of it until it becomes a severe disability. Ototoxicants are substances that may damage the inner ear by either affecting the structures in the ear itself or by affecting the nervous system. We have examined the possibility that ototoxicants may present a health hazard in association with environmental exposures, adding to existing knowledge of their proven hazards under medical therapeutic conditions or occupational activities. In addition to the already described human environmental ototoxicants, mainly organochlorines such as polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), hexachlorocyclohexane (HCH) and hexachlorobenzene (HCB), we have examined the ubiquitous chemical stressors phthalates, bisphenol A/S/F/, PFCs, flame retardants (FRs) and cadmium for potential ototoxic properties, both as single substances or as chemical mixtures. Our literature review confirmed that these chemicals may disturb thyroid hormones homeostasis, activate aryl hydrocarbon receptor (AhR), and induce oxidative stress, which in turn may initiate a chain of events resulting in impairment of cochlea and hearing loss. With regard to auditory plasticity, diagnostics of a mixture of effects of ototoxicants, potential interactions of chemical and physical agents with effects on hearing, parallel deterioration of hearing due to chemical exposures and ageing, metabolic diseases or obesity, even using specific methods as brainstem auditory evoked potentials (BAEP) or otoacoustic emissions (OAEs) registration, may be difficult, and establishment of concentration-response relationships problematic. This paper suggests the establishment of a class of environmental oxotoxicants next to the established classes of occupational and drug ototoxicants. This will help to properly manage risks associated with human exposure to chemical stressors with ototoxic properties and adequate regulatory measures.

The spatial distribution of congener-specific human PCB concentrations in a PCB-polluted region.

Serum PCB congener concentrations were measured in 602 adults living near a PCB pollution source in eastern Slovakia. We created isoconcentration maps for 21 PCB congeners by geocoding each participant's place of residence and kriging. Concentrations of PCB congeners were inversely associated with the distance of the participants' residence from the source of pollution. Congener-specific risk factors were derived, particularly for PCBs 52 and 153. We observed that the spatial distribution of serum concentrations was influenced by micro-climatic parameters and physicochemical properties of the congeners. PCB congener profiles strongly correlated with that of the PCB commercial product Delor 106, which was manufactured in the region. The isoconcentration maps indicate that the zones with the highest predicted congener concentration have a mean area of approximately 235.75±188.56km2 and the mean enrichment of concentration of congeners in serum in these zones is about 5.12±1.36. We estimate that depending on congener approximately 23,457±18,762 individuals with PCB concentrations exceeding health-based guidance values live in these zones.

Prenatal and Early Postnatal Exposure to Total Mercury and Methylmercury from Low Maternal Fish Consumption.

The aim of this study was to investigate the influence of low fish consumption on prenatal and early postnatal exposure to mercury species. The samples of umbilical cord blood and maternal milk as well as interviewer-administered questionnaires were collected from 142 Slovak mother-child pairs. The mean total mercury (THg) concentrations in cord blood and milk were 0.949 µg/L and 0.376 µg/kg, respectively. The mean methylmercury (MeHg) concentration in cord blood was 0.504 µg/L. Fish eaters had significantly higher cord blood MeHg concentrations than non-fish eaters (p = 0.030); no difference was found in milk or cord blood THg concentrations. The bivariate analysis showed a positive correlation between cord blood MeHg and consumption of sea fish and shellfish (rs = 0.320, p < 0.001); after adjustment for the potential confounders, the association was weakened (ß = 0.173, p = 0.059). Nevertheless, the decision tree method showed sea fish and shellfish consumption to be the best predictor of cord blood MeHg. Furthermore, a negative association was found between THg concentrations in maternal milk and freshwater fish consumption (ß = - 0.193, p = 0.017), which might indicate a beneficial effect of freshwater fish consumption. The results suggest there is a need for future research to investigate the benefits versus the adverse effects of low maternal fish consumption on child development.

Determinants of prenatal exposure to perfluoroalkyl substances in the Slovak birth cohort.

BACKGROUND: Perfluoroalkyl substances (PFASs) are man-made fluorinated compounds with endocrine-disrupting properties, detected in 99% of serum samples worldwide and associated with adverse childhood health outcomes. The aim of this study was to describe determinants of prenatal exposure to PFASs in Slovakia. METHODS: This study was based on Slovak multicentric prospective mother-child cohort PRENATAL (N = 796). Cord blood samples were collected within 2010-2012 and PFASs were analyzed in a subpopulation of 322 newborns. Concentrations of perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were measured in the samples of cord blood using an ultrahigh-performance liquid chromatography- mass spectrometry (U-HPLC-MS) method. From questionnaires, we obtained information on medical history of mother, socio-demographic factors, nutrition and environmental factors. Association between maternal characteristics and PFASs exposure was analyzed using multivariable linear regression models. RESULTS: The highest cord blood concentration (geometric mean ±â€¯SD) was observed for PFOA (0.79 ±â€¯2.21 ng/ml) followed by PFOS (0.36 ±â€¯2.56 ng/ml), PFNA (0.20 ±â€¯2.44 ng/ml) and PFHxS (0.07 ±â€¯2.36 ng/ml). Primiparity was associated with higher levels of all four PFAS: PFOS (exp. ß = 1.25; 95%CI[1.03; 1.53]), PFOA (exp. ß = 1.49; 95%CI[1.18; 1.89]), PFNA (exp. ß = 1.30; 95%CI[1.05; 1.60]) and PFHxS (exp. ß = 1.49; 95%CI [1.20; 1.86]). In addition, maternal age category 29 years and more was associated with higher PFNA and PFHxS levels (exp. ß = 1.27; 95%CI[1.04; 1.55] and exp. ß = 1.30; 95%CI[1.06; 1.60], respectively) and higher educational level of mother was associated with higher PFNA levels (exp. ß = 1.32; 95%CI[1.04; 1.68]). Higher fish consumption was associated with lower PFNA levels (exp. ß = 0.49; 95%CI[0.26; 0.92]). CONCLUSIONS: We observed that PFASs cord blood concentrations were comparable or lower than those measured in western or northern European countries. We identified parity as the main determinant of PFASs exposure in our population and maternal age and education as factors that might be associated with exposure to certain PFASs.

Prenatal and postnatal exposure to persistent organic pollutants and attention-deficit and hyperactivity disorder: a pooled analysis of seven European birth cohort studies.

Background: Attention-deficit/hyperactivity disorder (ADHD) is increasing worldwide for reasons largely unknown and environmental chemicals with neurotoxic properties, such as persistent organic pollutants (POPs), have been proposed to play a role. We investigated the association between prenatal and postnatal exposure to polychlorinated biphenyl-153 (PCB-153), p-p´-dichlorodiphenyldichloroethylene (p-p'-DDE) and hexachlorobenzene (HCB) and ADHD in childhood. Methods: We pooled seven European birth cohort studies encompassing 4437 mother-child pairs from the general population with concentrations of PCB-153, p-p´-DDE and HCB measured in cord blood, maternal blood or milk. We then calculated prenatal (birth) and postnatal (3, 6, 12 and 24 months) POP concentrations using a pharmacokinetic model. The operational definition of ADHD varied across cohorts and ranged from doctor diagnosis obtained from patient registries to maternal or teachers reports. We used multilevel (mixed) logistic regression models to estimate the associations between exposure to POPs at birth, 3, 6, 12 and 24 months and ADHD. Results: The global prevalence of ADHD in our study was 6%. The mean age at assessment of ADHD was 5.8 years (range: 3.8-9.5 years). We found no association between exposure to PCB-153, p-p´-DDE and HCB at any age point between birth and 24 months and ADHD, in the pooled analyses (pooled odds ratios ranging from 1.00 to 1.01). A number of sensitivity analyses gave basically the same results. Conclusions: In the largest study to date of 4437 children in seven European birth cohorts, we did not observe any association between either pre- or postnatal exposure (up to 24 months) to PCB-153, p-p´-DDE and HCB and the risk of ADHD before the age of 10 years.

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.

PCB exposure and potential future cancer incidence in Slovak children: an assessment from molecular finger printing by Ingenuity Pathway Analysis (IPA®) derived from experimental and epidemiological investigations.

The risk of cancer due to PCB exposure in humans is highly debated. In eastern Slovakia, high exposure of the population to organochlorines (especially PCBs) was associated with various disease and disorder pathways, viz., endocrine disruption, metabolic disorder & diabetes, and cancer, thereby disturbing several cellular processes, including protein synthesis, stress response, and apoptosis. We have evaluated a Slovak cohort (45-month children, at lower and higher levels of PCB exposure from the environment) for disease and disorder development to develop early disease cancer biomarkers that could shed new light on possible mechanisms for the genesis of cancers under such chemical exposures, and identify potential avenues for prevention.Microarray studies of global gene expression were conducted from the 45-month-old children on the Affymetrix platform followed by Ingenuity Pathway Analysis (IPA®) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR TaqMan low-density array (TLDA) was performed to further validate the selected genes on the whole blood cells of the most highly exposed children from the study cohort (n = 71). TP53, MYC, BCL2, and LRP12 differential gene expressions suggested strong relationships between potential future tumor promotion and PCB exposure in Slovak children. The IPA analysis further detected the most important signaling pathways, including molecular mechanism of cancers, prostate cancer signaling, ovarian cancer signaling, P53 signaling, oncostatin M signaling, and their respective functions (viz., prostate cancer, breast cancer, progression of tumor, growth of tumor, and non-Hodgkin's disease). The results suggest that PCB exposures, even at the early age of these children, may have lifelong consequences for the future development of chronic diseases.

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.

Partitioning of hexachlorobenzene between human milk and blood lipid.

In epidemiological studies on the toxic effects of prenatal exposure to hexachlorobenzene (HCB), researchers report HCB concentrations, either as wet-weight or per lipid weight basis, in matrices like breast milk, and maternal and cord blood. Conversion of exposures across matrices is needed for comparisons of concentrations and dose effect across cohorts. Using data from a birth cohort study in eastern Slovakia, we derived the maternal blood to cord blood HCB concentration ratio utilizing measured concentrations in 1027 paired maternal and cord blood samples, on a per-lipid basis. In addition to data from the Slovak study, the maternal milk to maternal serum ratio was summarized from 23 published studies on partitioning of HCB between human milk lipid and blood lipid. We identified two distinct groups of milk:blood ratios, those ≤0.45 and those ≥0.85. We assumed that using partition ratios ≤0.45 will underestimate HCB exposure estimates. Taking into account this precautionary measure, we suggest a conversion ratio of 1.21, which is the median of the 16 ratios identified in our literature review. We consider our estimate as conservative and providing appropriate safety in risk analysis.

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.

Exposure of children to phthalates and the impact of consumer practices in Slovakia.

Phthalates are environmental pollutants that can enter the human body by ingestion, inhalation and dermal absorption. Food constitutes the most important source of human exposure to these chemicals. The aim of our study was the biological monitoring of exposure to eight phthalate metabolites in children (n=107), 10-12 years of age, living in eastern Slovakia. Additionally, we analysed some associations between anthropometric measures, questionnaire data (i.e. eating and drinking habits, practice of personal care products) and concentrations of phthalate metabolites. Because of the short half-life of phthalates, within 24-48 h, we used 24-h recalls to assess dietary intakes. We used high-performance liquid chromatography and tandem mass spectrometry for the analysis of spot urine samples to determine concentrations of phthalate metabolites mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono-iso-butyl phthalate, mono-benzyl phthalate (MBzP), mono (2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono-carboxy pentyl and mono (2-ethylhexyl) phthalate (MEHP). We found statistically significant association between consumer practices and concentration of some phthalate metabolites, concretely consumption of milk and dairy products with MBzP and margarine with MEP (p<0.01 in both cases) and margarine with 5oxo-MEHP, hot beverages with 5OH-MEHP, baguettes and semifinished products with MEP (p<0.05 in all cases). Further, we found relationship between use of cosmetic products and phthalate concentrations, nail polish application and MEP and use of body lotion and MEHP (p<0.05 in both cases). We concluded that consumer practices (including eating and drinking habits and personal care) represent the substantial source of phthalate exposure in Slovak children.