Eleni Papadopoulou

Comprehensive Study of Human External Exposure to Organophosphate Flame Retardants via Air, Dust, and Hand Wipes: The Importance of Sampling and Assessment Strategy

We compared the human exposure to organophosphate flame retardants (PFRs) via inhalation, dust ingestion, and dermal absorption using different sampling and assessment strategies. Air (indoor stationary air and personal ambient air), dust (floor dust and surface dust), and hand wipes were sampled from 61 participants and their houses. We found that stationary air contains higher levels of ΣPFRs (median = 163 ng/m(3), IQR = 161 ng/m(3)) than personal air (median = 44 ng/m(3), IQR = 55 ng/m(3)), suggesting that the stationary air sample could generate a larger bias for inhalation exposure assessment. Tris(chloropropyl) phosphate isomers (ΣTCPP) accounted for over 80% of ΣPFRs in both stationary and personal air. PFRs were frequently detected in both surface dust (ΣPFRs median = 33 100 ng/g, IQR = 62 300 ng/g) and floor dust (ΣPFRs median = 20 500 ng/g, IQR = 30 300 ng/g). Tris(2-butoxylethyl) phosphate (TBOEP) accounted for 40% and 60% of ΣPFRs in surface and floor dust, respectively, followed by ΣTCPP (30% and 20%, respectively). TBOEP (median = 46 ng, IQR = 69 ng) and ΣTCPP (median = 37 ng, IQR = 49 ng) were also frequently detected in hand wipe samples. For the first time, a comprehensive assessment of human exposure to PFRs via inhalation, dust ingestion, and dermal absorption was conducted with individual personal data rather than reference factors of the general population. Inhalation seems to be the major exposure pathway for ΣTCPP and tris(2-chloroethyl) phosphate (TCEP), while participants had higher exposure to TBOEP and triphenyl phosphate (TPHP) via dust ingestion. Estimated exposure to ΣPFRs was the highest with stationary air inhalation (median =34 ng·kg bw(-1)·day(-1), IQR = 38 ng·kg bw(-1)·day(-1)), followed by surface dust ingestion (median = 13 ng·kg bw(-1)·day(-1), IQR = 28 ng·kg bw(-1)·day(-1)), floor dust ingestion and personal air inhalation. The median dermal exposure on hand wipes was 0.32 ng·kg bw(-1)·day(-1) (IQR = 0.58 ng·kg bw(-1)·day(-1)) for ΣTCPP. The selection of sampling and assessment strategies could significantly affect the results of exposure assessment.

In utero exposure to dioxins and dioxin-like compounds and anogenital distance in newborns and infants

Background: Anogenital distance in animals is used as a measure of fetal androgen action. Prenatal exposure to dioxins and dioxin-like compounds in rodents causes reproductive changes in male offspring and decreases anogenital distance. Objective: We assessed whether in utero exposure to dioxins and dioxin-like compounds adversely influences anogenital distance in newborns and young children (median age, 16 months; range, 1–31 months). Methods: We measured anogenital distance among participants of the “Rhea” mother–child cohort study in Crete and the Hospital del Mar (HMAR) cohort in Barcelona. Anogenital distance (AGD; anus to upper penis), anoscrotal distance (ASD; anus to scrotum), and penis width (PW) were measured in 119 newborn and 239 young boys; anoclitoral (ACD; anus to clitoris) and anofourchetal distance (AFD; anus to fourchette) were measured in 118 newborn and 223 young girls. We estimated plasma dioxin-like activity in maternal blood samples collected at delivery with the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX®) bioassay. Results: Anogenital distances were sexually dimorphic, being longer in males than females. Plasma dioxin-like activity was negatively associated with AGD in male newborns. The estimated change in AGD per 10 pg CALUX®–toxic equivalent/g lipid increase was –0.44 mm (95% CI: –0.80, –0.08) after adjusting for confounders. Negative but smaller and nonsignificant associations were observed for AGD in young boys. No associations were found in girls. Conclusions: Male infants may be susceptible to endocrine-disrupting effects of dioxins. Our findings are consistent with the experimental animal evidence used by the Food and Agriculture Organization/World Health Organization to set recommendations for human dioxin intake.

Anogenital Distances in Newborns and Children from Spain and Greece: Predictors, Tracking and Reliability

BACKGROUND Anogenital distance has been associated with prenatal exposure to chemicals with anti-androgenic effects. There are limited data in humans concerning descriptive patterns, predictors, and the reliability of measurement of anogenital distances. We examined anogenital distance measurements and their predictors in males and females and further estimated the reliability of these measurements. METHODS Anogenital distances were measured in repeated time periods among 352 newborns and 732 young children in two cohorts, one in Crete, Greece and one in Barcelona, Spain. Mixed effect models were used to estimate the between-children, between- and within-examiners variance, as well as the reliability coefficients. RESULTS Genitalia distances were longer in males than in females. Anogenital distances in both sexes increased rapidly from birth to 12 months, while the additional increase during the second year was small. Birthweight was associated with an increase of 1.9 mm/kg [95% CI 0.1, 3.8] (CI, confidence interval) in the anogenital distance measured from the anus to anterior base of the penis in newborn males, 2.9 mm/kg [95% CI 1.8, 3.9] in anoclitoral distance and 1.0 mm/kg [95% CI 0.0, 2.0] in anofourchettal distance in newborn females, after adjustment for gestational age. In children, body weight was the main predictor of all genitalia measurements. Moreover, anogenital distances at birth were associated with the corresponding distances at early childhood. High reliability coefficients (>90%) were found for all anogenital distances measurements in males and females. CONCLUSIONS Anogenital distances are strongly related to gestational age and birthweight and later, to growth. They track through early life and are highly reliable measures in both sexes.

Maternal dietary intake of dioxins and polychlorinated biphenyls and birth size in the Norwegian Mother and Child Cohort Study (MoBa)

Maternal diet not only provides essential nutrients to the developing fetus but is also a source of prenatal exposure to environmental contaminants. We investigated the association between dietary intake of dioxins and PCBs during pregnancy and birth size. The study included 50,651 women from the Norwegian Mother and Child Cohort Study (MoBa). Dietary information was collected by FFQs and intake estimates were calculated by combining food consumption and food concentration of dioxins, dioxin-like PCBs and non-dioxin-like PCBs. We used multivariable regression models to estimate the association between dietary intake of dioxins and PCBs and fetal growth. The contribution of fish and seafood intake during pregnancy was 41% for dietary dioxins and dioxin-like PCBs and 49% for dietary non-dioxin-like PCBs. Further stratified analysis by quartiles of seafood intake during pregnancy was conducted. We found an inverse dose-response association between dietary intake of dioxins and PCBs and fetal growth after adjustment for confounders. Newborns of mothers in the upper quartile of dioxin and dioxin-like PCBs intake had 62g lower birth weight (95% CI: -73, -50), 0.26cm shorter birth length (95% CI: -0.31, -0.20) and 0.10cm shorter head circumference (95% CI: -0.14, -0.06) than newborns of mothers in the lowest quartile of intake. Similar negative associations for intake of dioxins and dioxin-like PCBs were found after excluding women with intakes above the tolerable weekly intake (TWI=14pg TEQ/kg bw/week). The negative association of dietary dioxins and PCBs with fetal growth was weaker as seafood intake was increasing. No association was found between dietary dioxin and PCB intake and the risk for small-for-gestational age neonate. In conclusion, dietary intakes of dioxins and PCBs during pregnancy were negatively associated with fetal growth, even at intakes below the TWI.

Organic Food Consumption during Pregnancy and Hypospadias and Cryptorchidism at Birth: The Norwegian Mother and Child Cohort Study (MoBa)

Background The etiologies of the male urogenital anomalies hypospadias and cryptorchidism remain unclear. It has been suggested that maternal diet and environmental contaminants may affect the risk of these anomalies via placental or hormonal disturbances. Objectives We examined associations between organic food consumption during pregnancy and prevalence of hypospadias and cryptorchidism at birth. Methods Our study includes 35,107 women participating in the Norwegian Mother and Child Cohort Study (MoBa) who delivered a singleton male infant. Information about use of six groups of organically produced food (vegetables, fruit, bread/cereal, milk/dairy products, eggs, and meat) during pregnancy was collected by a food frequency questionnaire. Women who indicated that they sometimes, often, or mostly consumed organic foods in at least one of the six food groups were classified as organic food consumers in analyses. Hypospadias and cryptorchidism diagnoses were retrieved from the Medical Birth Registry of Norway. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression. Results Seventy-four male newborns were diagnosed with hypospadias (0.2%), and 151 with cryptorchidism (0.4%). Women who consumed any organic food during pregnancy were less likely to give birth to a boy with hypospadias (OR = 0.42; 95% CI: 0.25, 0.70, based on 21 exposed cases) than women who reported they never or seldom consumed organic food. Associations with specific organic foods were strongest for vegetable (OR = 0.36; 95% CI: 0.15, 0.85; 10 exposed cases) and milk/dairy (OR = 0.43; 95% CI: 0.17, 1.07; 7 exposed cases) consumption. No substantial association was observed for consumption of organic food and cryptorchidism. Conclusions Consumption of organically produced foods during pregnancy was associated with a lower prevalence of hypospadias in our study population. These findings were based on small numbers of cases and require replication in other study populations. Citation Brantsæter AL, Torjusen H, Meltzer HM, Papadopoulou E, Hoppin JA, Alexander J, Lieblein G, Roos G, Holten JM, Swartz J, Haugen M. 2016. Organic food consumption during pregnancy and hypospadias and cryptorchidism at birth: the Norwegian Mother and Child Cohort Study (MoBa). Environ Health Perspect 124:357–364; http://dx.doi.org/10.1289/ehp.1409518

Maternal diet, prenatal exposure to dioxin-like compounds and birth outcomes in a European prospective mother-child study (NewGeneris)

Maternal diet can result in exposure to environmental contaminants including dioxins which may influence foetal growth. We investigated the association between maternal diet and birth outcomes by defining a dioxin-rich diet. We used validated food frequency questionnaires to assess the diet of pregnant women from Greece, Spain, United Kingdom, Denmark and Norway and estimated plasma dioxin-like activity by the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR-CALUX®) bioassay in 604 maternal blood samples collected at delivery. We applied reduced rank regression to identify a dioxin-rich dietary pattern based on dioxin-like activity (DR-CALUX®) levels in maternal plasma, and calculated a dioxin-diet score as an estimate of adherence to this dietary pattern. In the five country population, dioxin-diet score was characterised by high consumption of red and white meat, lean and fatty fish, low-fat dairy and low consumption of salty snacks and high-fat cheese, during pregnancy. The upper tertile of the dioxin-diet score was associated with a change in birth weight of -121g (95% confidence intervals: -232, -10g) compared to the lower tertile after adjustment for confounders. A small non-significant reduction in gestational age was also observed (-1.4days, 95% CI: -3.8, 1.0days). Our results suggest that maternal diet might contribute to the exposure of the foetus to dioxins and dioxin-like compounds and may be related to reduced birth weight. More studies are needed to develop updated dietary guidelines for women of reproductive age, aiming to the reduction of dietary exposure to persistent organic pollutants as dioxins and dioxin-like compounds.

Evaluation of exposure to phthalate esters and DINCH in urine and nails from a Norwegian study population

Phthalate esters (PEs) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) used as additives in numerous consumer products are continuously released into the environment, leading to subsequent human exposure which might cause adverse health effects. The human biomonitoring approach allows the detection of PEs and DINCH in specific populations, by taking into account all possible routes of exposure (e.g. inhalation, transdermal and oral) and all relevant sources (e.g. air, dust, personal care products, diet). We have investigated the presence of nine PE and two DINCH metabolites and their exposure determinants in 61 adult residents of the Oslo area (Norway). Three urine spots and fingernails were collected from each participant according to established sampling protocols. Metabolite analysis was performed by LC-MS/MS. Metabolite levels in urine were used to back-calculate the total exposure to their corresponding parent compound. The primary monoesters, such as monomethyl phthalate (MMP, geometric mean 89.7ng/g), monoethyl phthalate (MEP, 104.8ng/g) and mono-n-butyl phthalate (MnBP, 89.3ng/g) were observed in higher levels in nails, whereas the secondary bis(2-ethylhexyl) phthalate (DEHP) and DINCH oxidative metabolites were more abundant in urine (detection frequency 84-100%). The estimated daily intakes of PEs and DINCH for this Norwegian population did not exceed the established tolerable daily intake and reference doses, and the cumulative risk assessment for combined exposure to plasticizers with similar toxic endpoints indicated no health concerns for the selected population. We found a moderate positive correlation between MEP levels in 3 urine spots and nails (range: 0.56-0.68). Higher frequency of personal care products use was associated with greater MEP concentrations in both urine and nail samples. Increased age, smoking, wearing plastic gloves during house cleaning, consuming food with plastic packaging and eating with hands were associated with higher levels in urine and nails for some of the metabolites. In contrast, frequent hair and hand washing was associated with lower urinary levels of monoisobutyl phthalate (MiBP) and mono(2-ethyl-5-hydroxyhexyl) phthalate (5-OH-MEHP), respectively.

Reliability of perfluoroalkyl substances in plasma of 100 women in two consecutive pregnancies

The potential toxicity of background exposure to perfluoroalkyl substances (PFASs) is currently under active investigation. Such investigations typically rely on a single measure of PFAS concentration, yet the longer-term reliability of a single measure has not been well characterized, especially among reproductive-aged women. Our aim was to investigate the association between PFAS plasma concentrations of 100 women in two consecutive pregnancies and explore changes in plasma concentration related to reproductive factors. The women in our study were enrolled in the Norwegian Mother and Child Cohort Study (MoBa) from 2003 to 2009. About half of them breastfed exclusively for 6 months and the rest of the participants did not breastfeed between the two consecutive pregnancies (median time between pregnancies: 18 months). Maternal blood was collected at mid-pregnancy and plasma was analyzed for 10 PFASs. Statistical analyses were restricted to 6 PFASs that were quantifiable in more than 80% of the samples. We estimated the correlation between repeated PFAS measurements, the percentage change between pregnancies and the effect of several reproductive factors in multivariate linear regression models of PFAS concentrations in the second pregnancy. The Pearson correlation coefficient between repeated PFAS measurements was, for perfluorooctane sulfonate (PFOS), 0.80; perfluorooctanoate (PFOA), 0.50; perfluorohexane sulfonate (PFHxS), 0.74; perfluorononanoate (PFNA), 0.39; perfluoroundecanoate (PFUnDA), 0.71; and perfluorodecanoate (PFDA), 0.60. Adjustment for maternal age, delivery year, and time and breastfeeding between pregnancies did not substantially affect the observed correlations. We found 44-47% median reductions in the concentrations of PFOS, PFOA and PFHxS between pregnancies, while the change in concentrations between pregnancies was smaller and more variable for PFNA, PFUnDA and PFDA. The variation in plasma concentrations in the second pregnancy was mainly accounted for by the concentration in the first pregnancy; for PFOS, PFOA, and PFNA, breastfeeding also accounted for a substantial proportion. In conclusion, we found the reliability of PFAS measurements in maternal plasma to be moderate to high, and in these data, several factors, especially breastfeeding, were related to plasma concentrations.

Assessment of dietary exposure to organohalogen contaminants, legacy and emerging flame retardants in a Norwegian cohort

Polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), emerging halogenated flame retardants (EHFRs) and organophosphate flame retardants (PFRs) were detected in 24h duplicate diet samples from a Norwegian cohort (n=61), with concentrations ranging from <method limit of quantification (MLQ)-0.64ng/g ww, <MLQ-0.70ng/g ww, <MLQ-0.93ng/g ww, <MLQ-0.14ng/g ww, and <MLQ-150ng/g ww, respectively. All studied contaminants were detected in the duplicate diet samples with detection frequencies (DF) ranging from 1.6 to 98%. The major contaminants were CB153 (median 0.042ng/g ww), α-HCH (median 0.22ng/g ww), BDE209 (median 0.45ng/g ww), ethyl hexyl diphenyl phosphate (EHDPHP) (median 3.0ng/g ww) and bis(2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate (BEH-TEBP) (<MLQ-0.14ng/g ww). Human dietary exposure assessment was conducted for each participant based on individual body weight and contaminant concentrations in their collected duplicate diet samples. The estimated median (95th percentile) dietary exposures for ΣPFR, ΣPCB, ΣOCP, ΣPBDE, and ΣEHFR were 87 (340), 5.8 (27), 11 (31), 1.3 (14), and <0.01 (3.4) ng/kgbw/day, respectively. The median and 95th percentile dietary exposures of most of the target analytes did not exceed the reference dose (RfD), except for PCBs where 16% of the participants exceeded the RfD. However, a relatively short period of such high intake is not expected to result in any adverse health effects. Participants of this cohort were exposed to higher levels of EHDPHP than any other FRs. Fish was the major dietary route for PCB, OCP and PBDE exposure, while meat was the main dietary exposure route for PFRs.

Maternal cell phone use during pregnancy and child behavioral problems in five birth cohorts

INTRODUCTION Previous studies have reported associations between prenatal cell phone use and child behavioral problems, but findings have been inconsistent and based on retrospective assessment of cell phone use. This study aimed to assess this association in a multi-national analysis, using data from three cohorts with prospective data on prenatal cell phone use, together with previously published data from two cohorts with retrospectively collected cell phone use data. METHODS We used individual participant data from 83,884 mother-child pairs in the five cohorts from Denmark (1996-2002), Korea (2006-2011), the Netherlands (2003-2004), Norway (2004-2008), and Spain (2003-2008). We categorized cell phone use into none, low, medium, and high, based on frequency of calls during pregnancy reported by the mothers. Child behavioral problems (reported by mothers using the Strengths and Difficulties Questionnaire or Child Behavior Checklist) were classified in the borderline/clinical and clinical ranges using validated cut-offs in children aged 5-7years. Cohort specific risk estimates were meta-analyzed. RESULTS Overall, 38.8% of mothers, mostly from the Danish cohort, reported no cell phone use during pregnancy and these mothers were less likely to have a child with overall behavioral, hyperactivity/inattention or emotional problems. Evidence for a trend of increasing risk of child behavioral problems through the maternal cell phone use categories was observed for hyperactivity/inattention problems (OR for problems in the clinical range: 1.11, 95%CI 1.01, 1.22; 1.28, 95%CI 1.12, 1.48, among children of medium and high users, respectively). This association was fairly consistent across cohorts and between cohorts with retrospectively and prospectively collected cell phone use data. CONCLUSIONS Maternal cell phone use during pregnancy may be associated with an increased risk for behavioral problems, particularly hyperactivity/inattention problems, in the offspring. The interpretation of these results is unclear as uncontrolled confounding may influence both maternal cell phone use and child behavioral problems.