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.

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.

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.

Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on cytochrome P450 1A1 and 1B1 gene expression in blood.

BACKGROUND: In the risk assessment of PCDDs, PCDFs, and dioxin-like (DL) PCBs, regulatory authorities support the use of the toxic equivalency factor (TEF)-scheme derived from a heterogeneous data set of the relative effect potency (REPs) estimates. OBJECTIVES: We sought to determine REPs for dioxin-like compounds (DLCs) using expression of cytochrome P450 (CYP) 1A1 and 1B1 mRNA in human peripheral blood mononuclear cells representing two different pathways. METHODS: We used a sex and age adjusted regression-based approach comparing the strength of association between each DLC and the cytochrome P450 (CYP) 1A1 and 1B1 mRNA expression in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. RESULTS: We calculated REPs based on CYP1A1 expression for 4 PCDDs, 8 PCDFs, and 1 PCB congener, and based on CYP1B1 expression for 5 PCDFs and 11 PCB congeners. REPs from CYP1A1 correlated with REPs previously derived from thyroid volume (ρ=0.85; p<0.001) and serum FT4 (ρ=0.77; p=0.009). The 13 log REPs from CYP1A1 correlated with log WHO-TEFs (r=0.63; p=0.015) and 11 log PCB REPs with PCB consensus toxicity factors (CTFs) for compounds with WHO-TEFs (r=0.80; p=0.003). The complete set of derived 56 log REPs correlated with the log CTFs (r=0.77; p=0.001) and log WHO-TEFs (r=0.81; p<0.001). CONCLUSIONS: REPs calculated from thyroid and cytochrome P450 endpoints realistically reflect human exposure scenarios because they are based on human chronic and low-dose exposures. While the CYP 1A1 seems more suitable for toxicity evaluation of PCDD/Fs, the CYP 1B1 is more apt for PCDFs and PCBs and reflects different pathways.

DPOAEs in infants developmentally exposed to PCBs show two differently time spaced exposure sensitive windows.

The study aim was to identify the timing of sensitive windows for ototoxicity related to perinatal exposure to PCBs. A total of 351 and 214 children from a birth cohort in eastern Slovakia underwent otoacoustic testing at 45 and 72 months, respectively, and distortion product otoacoustic emissions (DPOAEs) at 11 frequencies were recorded. Cord and child 6-, 16-, 45-, and 72- month blood samples were analyzed for PCB 153 concentration. The PCB 153 concentration-time profiles were approximated with a system model to calculate area under the PCB*time curves (AUCs) for specific time intervals (3 and 6 months for 45 and 72 months data, respectively). DPOAE amplitudes were correlated (Spearman) with cord serum PCB and AUCs, markers of prenatal and postnatal exposure, respectively. Two exposure critical windows were identified in infants, the first related to prenatal and early postnatal and the second to postnatal exposure to PCBs. Our data have shown tonotopicity, sexual dimorphism, and asymmetry in ototoxicity of PCBs.

Demographic, Reproductive, and Dietary Determinants of Perfluorooctane Sulfonic (PFOS) and Perfluorooctanoic Acid (PFOA) Concentrations in Human Colostrum.

To determine demographic, reproductive, and maternal dietary factors that predict perfluoroalkyl substance (PFAS) concentrations in breast milk, we measured perfluorooctane sulfonic (PFOS) and perfluorooctanoic acid (PFOA) concentrations, using liquid chromatography-mass spectrometry, in 184 colostrum samples collected from women participating in a cohort study in Eastern Slovakia between 2002 and 2004. During their hospital delivery stay, mothers completed a food frequency questionnaire, and demographic and reproductive data were also collected. PFOS and PFOA predictors were identified by optimizing multiple linear regression models using Akaike's information criterion (AIC). The geometric mean concentration in colostrum was 35.3 pg/mL for PFOS and 32.8 pg/mL for PFOA. In multivariable models, parous women had 40% lower PFOS (95% CI: -56 to -17%) and 40% lower PFOA (95% CI: -54 to -23%) concentrations compared with nulliparous women. Moreover, fresh/frozen fish consumption, longer birth intervals, and Slovak ethnicity were associated with higher PFOS and PFOA concentrations in colostrum. These results will help guide the design of future epidemiologic studies examining milk PFAS concentrations in relation to health end points in children.

The spatial distribution of human exposure to PCBs around a former production site in Slovakia.

We evaluated concentrations of 15 PCB congeners in blood serum of 2047 adults, 431 8-9-year old children and 1134 mother-child pairs born in 2001-2003. These subjects were long-standing residents living up to 70 km (to the north) and up to 50 km (to the south) of the former Chemko Strázske PCB production facility in the Michalovce district of Slovakia. We plotted serum concentration against distance from the plant both with and without consideration of the direction of their homes from the site. The decrease in exposure with distance could be described by an exponential function which was dependent on direction and climatic parameters. By kriging we created maps depicting predicted isoconcentration contours for sex- and age-adjusted serum concentration of ∑PCBs for the same group of children, adults and mothers. The principle of our risk analysis was to relate serum concentration data, reflecting PCB body burden, using the critical concentrations established by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES 2010) as thresholds below which the probability of effects on health is regarded as negligible. We conclude that 10 years ago, around 200,000 residents were at risk in this densely populated area. Exposure has since decreased but the mechanism for this has not yet been studied.

Ratio of cord to maternal serum PCB concentrations in relation to their congener-specific physicochemical properties.

The aim was to characterize placental transfer of some congeners of polychlorinated biphenyls (PCBs) and to relate human in utero exposure to these pollutants to their physicochemical properties. We included into the study 1134 births during the period 2002-2003 from two highly PCB contaminated districts in eastern Slovakia. Concentrations of 15 PCB congeners (IUPAC No. 28, 52, 101, 123(+149), 118, 114, 153, 105, 138(+163), 167, 156(+171), 157, 180, 170, and 189) in umbilical cord (C) and maternal serum (M) were determined. The C/M ratios were significantly related, either positively or inversely depending on parameter, to the logarithm of partition coefficient octanol-water (KOW), to fusion enthalpy at the melting point, molecular weight, water solubility, total surface area of the molecule, solvent accessible surface area, melting point, molar volume, and molecular electronegativity distance vector. We found an inverse association between logKOW and lipid adjusted logC/M (const=1.078, b1=-0.179, p<0.001, R(2)=0.039). Parameters evaluated were interrelated except fusion enthalpy at the melting point and electron affinity vs. solubility. We discuss the possible role of cholesterol as a transplacental transporter of PCBs.

Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on two thyroid outcomes.

BACKGROUND: Toxic equivalency factors (TEFs) are an important component in the risk assessment of dioxin-like human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these "intake" TEFs are commonly-but incorrectly-used by regulatory authorities to calculate "systemic" toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect. OBJECTIVES: We sought to determine relative effect potencies (REPs) for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum free thyroxine (FT4) concentration as the outcomes of interest. METHODS: We used a benchmark concentration and a regression-based approach to compare the strength of association between each dioxin-like compound and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. RESULTS: REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (ß)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, p = 0.01 and r = 0.62, p = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators. CONCLUSIONS: Our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of dioxin-like compounds.

Anthropometric, socioeconomic, and maternal health determinants of placental transfer of organochlorine compounds.

The aim of this study was to relate placental transfer, quantified by the cord to maternal serum concentration ratio (C/M), of five organochlorine pesticides (OCP) hexachlorobenzene (HCB), ß-hexachlorocyclohexane (ß-HCH), γ-hexachlorocyclohexane (γ-HCH) , p,p'-DDT, p,p'-DDE and 15 polychlorinated biphenyl (PCB) congeners (28, 52, 101, 105, 114, 118, 123(+149), 138(+163), 153, 156(+171), 157, 167, 170, 180, and 189) to anthropometric, socioeconomic, and maternal health characteristics. We included into the study 1,134 births during the period 2002-2004 from two districts in eastern Slovakia with high organochlorine concentrations relative to other areas of the world. Only concentrations >LOD were taken into account. Variables as age, weight and height of mothers, parity, ethnicity, alcohol consumption, illness during pregnancy, smoking during pregnancy, hypertension, respiratory diseases, rheumatoid arthritis and diabetes mellitus, and birth weight were related to C/M. Results of regression analyses showed that C/M was predicted by several factors studied. Positive associations were observed for gestational alcohol consumption, fewer illnesses during pregnancy, maternal age, and maternal weight. Caucasians had a greater C/M compared to Romani for wet weight data of congeners 170 and 180 and in contrast C/M for HCB was greater in Romani. Our results show that drinking mothers compared to abstaining expose their fetuses not only to alcohol but to an increased level of several PCB congeners. A straightforward explanation of associations between C/M shifts and factors studied is very difficult, however, with regard to the high lipophilicity of OCPs and PCBs, changes in their kinetics probably reflect lipid kinetics.

Assessment of exposure to PCB 153 from breast feeding and normal food intake in individual children using a system approach model.

Investigators have typically relied on a single or few discrete time points as measures of polychlorinated biphenyl (PCB) body burden, however health effects are more likely to be the result of integrative exposure in time, optionally expressed as an area under the time curve (AUC) of PCB serum concentration. Using data from a subgroup of 93 infants from a birth cohort in eastern Slovakia-a region highly polluted by PCBs-we fit a system type model, customized to our longitudinal measures of serum PCB concentrations in cord, 6, 16, and 45 month blood specimens. The most abundant congener, PCB 153, was chosen for modeling purposes. In addition to currently used methods of exposure assessment, our approach estimates a concentration time profile for each subject, taking into account mean residence time of PCB 153 molecules in the body, duration of breast feeding, hypothetical PCB 153 concentration in steady-state without breast feeding and alternately without normal food intake. Hypothetical PCB 153 concentration in steady-state without normal food intake correlates with AUC (r=0.84, p<0.001) as well as with duration of breast feeding (r=0.64, p<0.001). It makes possible to determine each subject's exposure profile expressed as AUC of PCBs serum concentration with a minimum model parameters. PCB body burden in most infants was strongly associated with duration of breast feeding in most, but not all children, was apparent from model output.