Publications by authors named "Line S Haug"

37 Publications

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and associations with attention-deficit/hyperactivity disorder and autism spectrum disorder in children.

Environ Res 2021 Jul 19:111692. Epub 2021 Jul 19.

Division of Mental and Physical Health, Norwegian Institute of Public Health, PO Box 222, Skøyen, N-0213, Oslo, Norway.

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent.

Objectives: We investigated whether prenatal exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD).

Methods: This study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach.

Results: Odds of ASD was significantly elevated in PFOA quartile 2 [OR = 1.71 (95% CI: 1.20, 2.45)] compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 [OR = 1.54 (95% CI: 1.16, 2.04)] compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD [OR = 0.76 (95% CI: 0.64, 0.90)] as well as the carboxylate mixture [OR = 0.79 (95% CI: 0.68, 0.93)] and the sulfonate mixture [OR = 0.84 (95% CI: 0.73, 0.96)].

Conclusion: Prenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development.
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http://dx.doi.org/10.1016/j.envres.2021.111692DOI Listing
July 2021

The early-life exposome and epigenetic age acceleration in children.

Environ Int 2021 Oct 15;155:106683. Epub 2021 Jun 15.

ISGlobal, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain. Electronic address:

The early-life exposome influences future health and accelerated biological aging has been proposed as one of the underlying biological mechanisms. We investigated the association between more than 100 exposures assessed during pregnancy and in childhood (including indoor and outdoor air pollutants, built environment, green environments, tobacco smoking, lifestyle exposures, and biomarkers of chemical pollutants), and epigenetic age acceleration in 1,173 children aged 7 years old from the Human Early-Life Exposome project. Age acceleration was calculated based on Horvath's Skin and Blood clock using child blood DNA methylation measured by Infinium HumanMethylation450 BeadChips. We performed an exposure-wide association study between prenatal and childhood exposome and age acceleration. Maternal tobacco smoking during pregnancy was nominally associated with increased age acceleration. For childhood exposures, indoor particulate matter absorbance (PM) and parental smoking were nominally associated with an increase in age acceleration. Exposure to the organic pesticide dimethyl dithiophosphate and the persistent pollutant polychlorinated biphenyl-138 (inversely associated with child body mass index) were protective for age acceleration. None of the associations remained significant after multiple-testing correction. Pregnancy and childhood exposure to tobacco smoke and childhood exposure to indoor PM may accelerate epigenetic aging from an early age.
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http://dx.doi.org/10.1016/j.envint.2021.106683DOI Listing
October 2021

Metal and essential element concentrations during pregnancy and associations with autism spectrum disorder and attention-deficit/hyperactivity disorder in children.

Environ Int 2021 07 22;152:106468. Epub 2021 Mar 22.

Division of Mental and Physical Health, Norwegian Institute of Public Health, PO Box 222 Skøyen, 0213 Oslo, Norway.

Background: Prenatal exposure to toxic metals or variations in maternal levels of essential elements during pregnancy may be a risk factor for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring.

Objectives: We investigated whether maternal levels of toxic metals and essential elements measured in mid-pregnancy, individually and as mixtures, were associated with childhood diagnosis of ADHD or ASD.

Methods: This study is based on the Norwegian Mother, Father and Child Cohort Study and included 705 ADHD cases, 397 ASD cases and 1034 controls. Cases were identified through linkage with the Norwegian Patient Registry. Maternal concentrations of 11 metals/elements were measured in blood at week 17 of gestation; cadmium; cesium; cobalt; copper; lead; magnesium; manganese; selenium; zinc; total arsenic; and total mercury. Multivariable adjusted logistic regression models were used to examine associations between quartile levels of individual metals/elements and outcomes. We also investigated non-linear associations using restricted cubic spline models. The joint effects of the metal/element mixture on ASD and ADHD diagnoses were estimated using a quantile-based g-computation approach.

Results: For ASD, we identified positive associations (increased risks) in the second quartile of arsenic [OR = 1.77 (CI: 1.26, 2.49)] and the fourth quartiles of cadmium and manganese [OR = 1.57 (CI: 1.07 2.31); OR = 1.84 (CI: 1.30, 2.59)], respectively. In addition, there were negative associations between cesium, copper, mercury, and zinc and ASD. For ADHD, we found increased risk in the fourth quartiles of cadmium and magnesium [OR = 1.59 (CI: 1.15, 2.18); [OR = 1.42 (CI: 1.06, 1.91)]. There were also some negative associations, among others with mercury. In addition, we identified non-linear associations between ASD and arsenic, mercury, magnesium, and lead, and between ADHD and arsenic, copper, manganese, and mercury. There were no significant findings in the mixture approach analyses.

Conclusion: Results from the present study show several associations between levels of metals and elements during gestation and ASD and ADHD in children. The most notable ones involved arsenic, cadmium, copper, mercury, manganese, magnesium, and lead. Our results suggest that even population levels of these compounds may have negative impacts on neurodevelopment. As we observed mainly similarities among the metals' and elements' impact on ASD and ADHD, it could be that the two disorders share some neurochemical and neurodevelopmental pathways. The results warrant further investigation and replication, as well as studies of combined effects of metals/elements and mechanistic underpinnings.
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http://dx.doi.org/10.1016/j.envint.2021.106468DOI Listing
July 2021

Biomarkers, matrices and analytical methods targeting human exposure to chemicals selected for a European human biomonitoring initiative.

Environ Int 2021 01 20;146:106082. Epub 2020 Nov 20.

Norwegian Institute of Public Health, Norway. Electronic address:

The major purpose of human biomonitoring is the mapping and assessment of human exposure to chemicals. The European initiative HBM4EU has prioritized seven substance groups and two metals relevant for human exposure: Phthalates and substitutes (1,2-cyclohexane dicarboxylic acid diisononyl ester, DINCH), bisphenols, per- and polyfluoroalkyl substances (PFASs), halogenated and organophosphorous flame retardants (HFRs and OPFRs), polycyclic aromatic hydrocarbons (PAHs), arylamines, cadmium and chromium. As a first step towards comparable European-wide data, the most suitable biomarkers, human matrices and analytical methods for each substance group or metal were selected from the scientific literature, based on a set of selection criteria. The biomarkers included parent compounds of PFASs and HFRs in serum, of bisphenols and arylamines in urine, metabolites of phthalates, DINCH, OPFRs and PAHs in urine as well as metals in blood and urine, with a preference to measure Cr in erythrocytes representing Cr (VI) exposure. High performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was the method of choice for bisphenols, PFASs, the HFR hexabromocyclododecane (HBCDD), phenolic HFRs as well as the metabolites of phthalates, DINCH, OPFRs and PAHs in urine. Gas chromatographic (GC) methods were selected for the remaining compounds, e.g. GC-low resolution MS with electron capture negative ionization (ECNI) for HFRs. Both GC-MS and LC-MS/MS were suitable for arylamines. New developments towards increased applications of GC-MS/MS may offer alternatives to GC-MS or LC-MS/MS approaches, e.g. for bisphenols. The metals were best determined by inductively coupled plasma (ICP)-MS, with the particular challenge of avoiding interferences in the Cd determination in urine. The evaluation process revealed research needs towards higher sensitivity and non-invasive sampling as well as a need for more stringent quality assurance/quality control applications and assessments.
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http://dx.doi.org/10.1016/j.envint.2020.106082DOI Listing
January 2021

Corrigendum to "Multi-pathway human exposure assessment of phthalate esters and DINCH" [Environ. Int. 112 (2018) 115-126].

Environ Int 2020 Oct 27;143:106071. Epub 2020 Aug 27.

Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.envint.2020.106071DOI Listing
October 2020

Early-Life Environmental Exposures and Childhood Obesity: An Exposome-Wide Approach.

Environ Health Perspect 2020 06 24;128(6):67009. Epub 2020 Jun 24.

Norwegian Institute of Public Health, Oslo, Norway.

Background: Chemical and nonchemical environmental exposures are increasingly suspected to influence the development of obesity, especially during early life, but studies mostly consider single exposure groups.

Objectives: Our study aimed to systematically assess the association between a wide array of early-life environmental exposures and childhood obesity, using an exposome-wide approach.

Methods: The HELIX (Human Early Life Exposome) study measured child body mass index (BMI), waist circumference, skinfold thickness, and body fat mass in 1,301 children from six European birth cohorts age 6-11 y. We estimated 77 prenatal exposures and 96 childhood exposures (cross-sectionally), including indoor and outdoor air pollutants, built environment, green spaces, tobacco smoking, and biomarkers of chemical pollutants (persistent organic pollutants, metals, phthalates, phenols, and pesticides). We used an exposure-wide association study (ExWAS) to screen all exposure-outcome associations independently and used the deletion-substitution-addition (DSA) variable selection algorithm to build a final multiexposure model.

Results: The prevalence of overweight and obesity combined was 28.8%. Maternal smoking was the only prenatal exposure variable associated with higher child BMI (-score increase of 0.28, 95% confidence interval: 0.09, 0.48, for active vs. no smoking). For childhood exposures, the multiexposure model identified particulate and nitrogen dioxide air pollution inside the home, urine cotinine levels indicative of secondhand smoke exposure, and residence in more densely populated areas and in areas with fewer facilities to be associated with increased child BMI. Child blood levels of copper and cesium were associated with higher BMI, and levels of organochlorine pollutants, cobalt, and molybdenum were associated with lower BMI. Similar results were found for the other adiposity outcomes.

Discussion: This first comprehensive and systematic analysis of many suspected environmental obesogens strengthens evidence for an association of smoking, air pollution exposure, and characteristics of the built environment with childhood obesity risk. Cross-sectional biomarker results may suffer from reverse causality bias, whereby obesity status influenced the biomarker concentration. https://doi.org/10.1289/EHP5975.
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http://dx.doi.org/10.1289/EHP5975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313401PMC
June 2020

Perfluoroalkyl substances (PFASs) in white whales (Delphinapterus leucas) from Svalbard - A comparison of concentrations in plasma sampled 15 years apart.

Environ Pollut 2020 Aug 5;263(Pt A):114497. Epub 2020 Apr 5.

Norwegian Polar Institute, Tromsø, Norway.

The objective of the present study was to investigate recent concentrations of perfluoroalkyl substances (PFASs) in white whales (Delphinapterus leucas) from Svalbard and compare them to concentrations found in white whales sampled from that same area 15 years ago. Plasma collected from live-captured white whales from two time periods (2013-2014, n = 9, and 1996-2001, n = 11) were analysed for 19 different PFASs. The 11 PFASs detected included seven C-C perfluoroalkyl carboxylates (PFCAs) and three C-C perfluoroalkyl sulfonates (PFSAs) as well as perfluorooctane sulfonamide (FOSA). Recent plasma concentrations (2013-2014) of the dominant PFAS in white whales, perfluorooctane sulfonate (PFOS; geometric mean = 22.8 ng/mL), was close to an order of magnitude lower than reported in polar bears (Ursus maritimus) from Svalbard. PFOS concentrations in white whales were about half the concentrations in harbour (Phoca vitulina) and ringed (Pusa hispida) seals, similar to hooded seals (Cystophora cristata) and higher than in walruses (Odobenus rosmarus) from that same area. From 1996 to 2001 to 2013-2014, plasma concentrations of PFOS decreased by 44%, whereas four C PFCAs and total PFCAs increased by 35-141%. These results follow a similar trend to what has been reported in other studies of Arctic marine mammals from Svalbard. The most dramatic change has been the decline of PFOS concentrations since 2000, corresponding to the production phase-out of PFOS and related compounds in many countries around the year 2000 and a global restriction on these substances in 2009. Still, the continued dominance of PFOS in white whales, and increasing concentration trends for several PFCAs, even though exposure is relatively low, calls for continued monitoring of concentrations of both PFCAs and PFSAs and investigation of biological effects.
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http://dx.doi.org/10.1016/j.envpol.2020.114497DOI Listing
August 2020

Association between the pregnancy exposome and fetal growth.

Int J Epidemiol 2020 04;49(2):572-586

Inserm, CNRS, University Grenoble Alpes, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, IAB, Grenoble, France.

Background: Several environmental contaminants were shown to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias and confounding by co-exposures. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. We aimed to characterize associations of fetal growth with the pregnancy chemical and external exposomes.

Methods: Within the Human Early-Life Exposome project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1287 mother-child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure measurement error and tested for exposure-exposure and sex-exposure interactions.

Results: The DSA model identified lead blood level, which was associated with a 97 g birth weight decrease for each doubling in lead concentration. No exposure passed the multiple testing-corrected significance threshold of ExWAS; without multiple testing correction, this model was in favour of negative associations of lead, fine particulate matter concentration and absorbance with birth weight, and of a positive sex-specific association of parabens with birth weight in boys. No two-way interaction between exposure variables was identified.

Conclusions: This first large-scale exposome study of fetal growth simultaneously considered >100 environmental exposures. Compared with single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation.
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http://dx.doi.org/10.1093/ije/dyaa017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266545PMC
April 2020

Prenatal exposure to perfluoroalkyl substances and associations with symptoms of attention-deficit/hyperactivity disorder and cognitive functions in preschool children.

Int J Hyg Environ Health 2020 01 22;223(1):80-92. Epub 2019 Oct 22.

Norwegian Institute of Public Health, PO Box 222, Skøyen, N-0213, Oslo, Norway.

Background: Perfluoroalkyl substances (PFASs) are persistent organic pollutants that are suspected to be neurodevelopmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We investigated the associations between prenatal exposure to PFASs and symptoms of attention-deficit/hyperactivity disorder (ADHD) and cognitive functioning (language skills, estimated IQ and working memory) in preschool children, as well as effect modification by child sex.

Material And Methods: This study included 944 mother-child pairs enrolled in a longitudinal prospective study of ADHD symptoms (the ADHD Study), with participants recruited from The Norwegian Mother, Father and Child Cohort Study (MoBa). Boys and girls aged three and a half years, participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview, Child Development Inventory and Stanford-Binet (5th revision). Prenatal levels of 19 PFASs were measured in maternal blood at week 17 of gestation. Multivariable adjusted regression models were used to examine exposure-outcome associations with two principal components extracted from the seven detected PFASs. Based on these results, we performed regression analyses of individual PFASs categorized into quintiles.

Results: PFAS component 1 was mainly explained by perfluoroheptane sulfonate (PFHpS), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorooctanoic acid (PFOA). PFAS component 2 was mainly explained by perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and perfluorononanoic acid (PFNA). Regression models showed a negative association between PFAS component 1 and nonverbal working memory [β = -0.08 (CI: -0.12, -0.03)] and a positive association between PFAS component 2 and verbal working memory [β = 0.07 (CI: 0.01, 0.12)]. There were no associations with ADHD symptoms, language skills or IQ. For verbal working memory and PFAS component 2, we found evidence for effect modification by child sex, with associations only for boys. The results of quintile models with individual PFASs, showed the same pattern for working memory as the results in the component regression analyses. There were negative associations between nonverbal working memory and quintiles of PFOA, PFNA, PFHxS, PFHpS and PFOS and positive associations between verbal working memory and quintiles of PFOA, PFNA, PFDA and PFUnDA, with significant relationships mainly in the highest concentration groups.

Conclusions: Based on our results, we did not find consistent evidence to conclude that prenatal exposure to PFASs are associated with ADHD symptoms or cognitive dysfunctions in preschool children aged three and a half years, which is in line with the majority of studies in this area. Our results showed some associations between PFASs and working memory, particularly negative relationships with nonverbal working memory, but also positive relationships with verbal working memory. The relationships were weak, as well as both positive and negative, which suggest no clear association - and need for replication.
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http://dx.doi.org/10.1016/j.ijheh.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922090PMC
January 2020

Per- and polyfluoroalkyl substances (PFASs) modify lung surfactant function and pro-inflammatory responses in human bronchial epithelial cells.

Toxicol In Vitro 2020 Feb 16;62:104656. Epub 2019 Sep 16.

Department of Toxicology and Risk Assessment, Division for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway. Electronic address:

The toxicity of some per- and polyfluoroalkyl substances (PFASs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) has been studied thoroughly, showing that systemic PFASs targets the lungs. However, regulators lack data to assess the impact of other PFASs on the lungs and alternative methods to test substances for lung toxicity are needed. We combined two in vitro models to assess toxicity to the respiratory system; i) a lung surfactant (LS) function assay to assess the acute inhalation toxicity potential, and ii) a cell model with human bronchial epithelial cells to study pro-inflammatory potential and modulation of inflammatory responses. We tested salts of four PFASs: perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), PFOS, and PFOA as well as the fluorotelomer 8:2 FTOH. The results show that PFHxS, PFOA and PFOS can inhibit LS function. High PFOS concentrations induced a pro-inflammatory response, measured as increased IL-1α/β release. Moderate concentrations of PFOS suppressed release of the chemokines CXCL8 and CXCL10, whereas both PFOS and PFOA stimulated the release of the pro-inflammatory cytokine IL-1β in immune stimulated human bronchial epithelial cells. These findings support the concern that some PFASs may increase the risk of acute lung toxicity and of airway infections.
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http://dx.doi.org/10.1016/j.tiv.2019.104656DOI Listing
February 2020

Socioeconomic position and exposure to multiple environmental chemical contaminants in six European mother-child cohorts.

Int J Hyg Environ Health 2019 06 19;222(5):864-872. Epub 2019 Apr 19.

ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain. Electronic address:

Background: Human exposure to environmental chemical contaminants at critical periods of development can lead to lifelong health consequences. Traditionally, socioeconomically disadvantaged groups are thought to experience higher contaminant exposures; however, this relationship may not hold for all contaminants.

Methods: Using data from six European birth cohorts (1301 mother-child pairs), we determined biomarkers of exposure to 41 contaminants in biological samples from children (6-12 years) and their mothers during pregnancy, including organochlorine compounds (OCs), polybrominated diphenyl ethers (PBDEs), per- and polyfluoroalkyl substances (PFASs), metals, phthalate metabolites, phenols, and organophosphate (OP) pesticide metabolites. We analyzed these biomarkers with several socioeconomic position (SEP) indicators (maternal education, employment status and family affluence scale).

Results: Higher SEP was associated with higher concentrations of several chemicals during pregnancy, including certain PFASs, mercury, arsenic, several phenols, and OP pesticides. Similarly, childhood concentrations of OCs, PFASs, mercury, arsenic, and bisphenol A were higher in higher SEP groups. Conversely, cadmium exposure during pregnancy and exposure to lead and phthalate metabolites in childhood were higher in lower SEP. Principal components representing multiple pollutant exposures showed similar association with SEP.

Conclusions: This study demonstrates that environmental chemical contaminant exposure during fetal and childhood life is not exclusively associated to lower SEP and that for several contaminants higher SEP groups incur higher exposure levels.
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http://dx.doi.org/10.1016/j.ijheh.2019.04.002DOI Listing
June 2019

Early-life exposome and lung function in children in Europe: an analysis of data from the longitudinal, population-based HELIX cohort.

Lancet Planet Health 2019 02 6;3(2):e81-e92. Epub 2019 Feb 6.

Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Inserm, CNRS, University Grenoble Alpes, Institute for Advanced Biosciences (IAB), U1209 Joint Research Center, Grenoble, France. Electronic address:

Background: Several single-exposure studies have documented possible effects of environmental factors on lung function, but none has relied on an exposome approach. We aimed to evaluate the association between a broad range of prenatal and postnatal lifestyle and environmental exposures and lung function in children.

Methods: In this analysis, we used data from 1033 mother-child pairs from the European Human Early-Life Exposome (HELIX) cohort (consisting of six existing longitudinal birth cohorts in France, Greece, Lithuania, Norway, Spain, and the UK of children born between 2003 and 2009) for whom a valid spirometry test was recorded for the child. 85 prenatal and 125 postnatal exposures relating to outdoor, indoor, chemical, and lifestyle factors were assessed, and lung function was measured by spirometry in children at age 6-12 years. Two agnostic linear regression methods, a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering exposures independently, were applied to test the association with forced expiratory volume in 1 s percent predicted values (FEV%). We tested for two-way interaction between exposures and corrected for confounding by co-exposures.

Findings: In the 1033 children (median age 8·1 years, IQR 6·5-9·0), mean FEV% was 98·8% (SD 13·2). In the ExWAS, prenatal perfluorononanoate (p=0·034) and perfluorooctanoate (p=0·030) exposures were associated with lower FEV%, and inverse distance to nearest road during pregnancy (p=0·030) was associated with higher FEV%. Nine postnatal exposures were associated with lower FEV%: copper (p=0·041), ethyl-paraben (p=0·029), five phthalate metabolites (mono-2-ethyl 5-carboxypentyl phthalate [p=0·016], mono-2-ethyl-5-hydroxyhexyl phthalate [p=0·023], mono-2-ethyl-5-oxohexyl phthalate [p=0·0085], mono-4-methyl-7-oxooctyl phthalate [p=0·040], and the sum of di-ethylhexyl phthalate metabolites [p=0·014]), house crowding (p=0·015), and facility density around schools (p=0·027). However, no exposure passed the significance threshold when corrected for multiple testing in ExWAS, and none was selected with the DSA algorithm, including when testing for exposure interactions.

Interpretation: Our systematic exposome approach identified several environmental exposures, mainly chemicals, that might be associated with lung function. Reducing exposure to these ubiquitous chemicals could help to prevent the development of chronic respiratory disease.

Funding: European Community's Seventh Framework Programme (HELIX project).
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http://dx.doi.org/10.1016/S2542-5196(19)30010-5DOI Listing
February 2019

The early-life exposome: Description and patterns in six European countries.

Environ Int 2019 02 6;123:189-200. Epub 2018 Dec 6.

Team of Environmental Epidemiology, IAB, Institute for Advanced Biosciences, Inserm, CNRS, CHU-Grenoble-Alpes, University Grenoble-Alpes, Grenoble, France.

Characterization of the "exposome", the set of all environmental factors that one is exposed to from conception onwards, has been advocated to better understand the role of environmental factors on chronic diseases. Here, we aimed to describe the early-life exposome. Specifically, we focused on the correlations between multiple environmental exposures, their patterns and their variability across European regions and across time (pregnancy and childhood periods). We relied on the Human Early-Life Exposome (HELIX) project, in which 87 environmental exposures during pregnancy and 122 during the childhood period (grouped in 19 exposure groups) were assessed in 1301 pregnant mothers and their children at 6-11 years in 6 European birth cohorts. Some correlations between exposures in the same exposure group reached high values above 0.8. The median correlation within exposure groups was >0.3 for many exposure groups, reaching 0.69 for water disinfection by products in pregnancy and 0.67 for the meteorological group in childhood. Median correlations between different exposure groups rarely reached 0.3. Some correlations were driven by cohort-level associations (e.g. air pollution and chemicals). Ten principal components explained 45% and 39% of the total variance in the pregnancy and childhood exposome, respectively, while 65 and 90 components were required to explain 95% of the exposome variability. Correlations between maternal (pregnancy) and childhood exposures were high (>0.6) for most exposures modeled at the residential address (e.g. air pollution), but were much lower and even close to zero for some chemical exposures. In conclusion, the early life exposome was high dimensional, meaning that it cannot easily be measured by or reduced to fewer components. Correlations between exposures from different exposure groups were much lower than within exposure groups, which have important implications for co-exposure confounding in multiple exposure studies. Also, we observed the early life exposome to be variable over time and to vary by cohort, so measurements at one time point or one place will not capture its complexities.
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http://dx.doi.org/10.1016/j.envint.2018.11.067DOI Listing
February 2019

Determinants of the urinary and serum metabolome in children from six European populations.

BMC Med 2018 11 8;16(1):202. Epub 2018 Nov 8.

Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK.

Background: Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment-health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project ( http://www.projecthelix.eu ).

Methods: Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6-11) recruited from birth cohorts in six European countries were measured using high-throughput H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit).

Results: We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythreonic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum.

Conclusions: We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children.
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http://dx.doi.org/10.1186/s12916-018-1190-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223046PMC
November 2018

Variability of urinary concentrations of non-persistent chemicals in pregnant women and school-aged children.

Environ Int 2018 12 6;121(Pt 1):561-573. Epub 2018 Oct 6.

ISGlobal, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain; Universitat Pompeu Fabra, Barcelona, Spain.

Background: Exposome studies are challenged by exposure misclassification for non-persistent chemicals, whose temporal variability contributes to bias in dose-response functions.

Objectives: We evaluated the variability of urinary concentrations of 24 non-persistent chemicals: 10 phthalate metabolites, 7 phenols, 6 organophosphate (OP) pesticide metabolites, and cotinine, between weeks from different pregnancy trimesters in pregnant women, and between days and between seasons in children.

Methods: 154 pregnant women and 152 children from six European countries were enrolled in 2014-2015. Pregnant women provided three urine samples over a day (morning, midday, and night), for one week in the 2nd and 3rd pregnancy trimesters. Children provided two urines a day (morning and night), over two one-week periods, six months apart. We pooled all samples for a given subject that were collected within a week. In children, we also made four daily pools (combining morning and night voids) during the last four days of the first follow-up week. Pools were analyzed for all 24 metabolites of interest. We calculated intraclass-correlation coefficients (ICC) and estimated the number of pools needed to obtain an ICC above 0.80.

Results: All phthalate metabolites and phenols were detected in >90% of pools whereas certain OP pesticide metabolites and cotinine were detected in <43% of pools. We observed fair (ICC = 0.40-0.59) to good (0.60-0.74) between-day reliability of the pools of two samples in children for all chemicals. Reliability was poor (<0.40) to fair between trimesters in pregnant women and between seasons in children. For most chemicals, three daily pools of two urines each (for weekly exposure windows) and four weekly pools of 15-20 urines each would be necessary to obtain an ICC above 0.80.

Conclusions: This quantification of the variability of biomarker measurements of many non-persistent chemicals during several time windows shows that for many of these compounds a few dozen samples are required to accurately assess exposure over periods encompassing several trimesters or months.
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http://dx.doi.org/10.1016/j.envint.2018.09.046DOI Listing
December 2018

Menstrual cycle characteristics as determinants of plasma concentrations of perfluoroalkyl substances (PFASs) in the Norwegian Mother and Child Cohort (MoBa study).

Environ Res 2018 10 4;166:78-85. Epub 2018 Jun 4.

National Institute for Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Durham, NC, USA.

Introduction: Perfluoroalkyl substances (PFASs) are fluorinated organic compounds that have been used in a variety of industrial and consumer applications. Menstruation is implicated as a possible route of elimination for PFASs in women. The overall purpose of this study was to examine menstrual cycle characteristics as determinants of plasma PFAS concentrations in women.

Methods: Our study sample consisted of 1977 pregnant women from the Norwegian Mother and Child Cohort (MoBa) study. The women were asked about menstrual cycle regularity in the year before the pregnancy and typical menstrual cycle length as well as other demographic and reproductive characteristics in a questionnaire completed during the pregnancy. Blood samples were collected around 17-18 weeks gestation and PFAS concentrations were measured in plasma. We examined the association between menstrual cycle characteristics and seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)) using multiple linear regression, adjusted for age, pre-pregnancy body mass index, smoking, education, income, parity, oral contraceptive use, inter-pregnancy interval, and breastfeeding duration.

Results: Irregular cycles were not associated with PFAS concentrations. Overall, we found no evidence of associations between menstrual cycle length and PFAS concentrations. In subgroup analyses we found some evidence, among parous women, of decreased PFHpS and PFOS with short menstrual cycles; we also found, among recent OC users (in the 12 months before the questionnaire) increased PFNA and PFUnDA with long cycle length. Limitations of our study include misclassification of menstrual cycle characteristics, small sample sizes in the sub-group analyses, and a lack of information on duration and volume of menses.

Conclusions: In the entire study sample, we found little evidence of menstrual cycle characteristics as determinants of PFAS concentrations. However, we observed some associations between cycle length and PFAS concentrations with some select PFAS compounds in subgroup analyses.
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http://dx.doi.org/10.1016/j.envres.2018.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174531PMC
October 2018

Oral contraceptive use as a determinant of plasma concentrations of perfluoroalkyl substances among women in the Norwegian Mother and Child Cohort (MoBa) study.

Environ Int 2018 03 20;112:156-164. Epub 2017 Dec 20.

Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston, School of Public Health in San Antonio, San Antonio, TX, USA; Southwest Center for Occupational and Environmental Health, The University of Texas Health Science Center at Houston, School of Public Health, Houston, TX, USA. Electronic address:

Objective: Because oral contraceptives (OC) tends to lessen menstrual fluid loss - a route of excretion for perfluoroalkyl substances (PFASs) - we hypothesized that such use would be positively associated with PFAS concentrations.

Methods: This analysis was based on the Norwegian Mother and Child Cohort (MoBa) study. We included 1090 women from two previous substudies of women enrolled from 2003 to 2007. Characteristics of OC use were obtained at baseline: use in the past 12months, duration and recency of use, age at first use. We examined log-transformed plasma concentrations of seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)). Linear regression analyses, adjusted for maternal age, menstrual cycle length, parity, and education, were used to examine whether OC use characteristics were determinants of PFAS concentrations.

Results: Except for PFDA and PFUnDA, women who used OCs in the 12months preceding the baseline interview had 12.9-35.7% higher PFAS concentrations than never OC users. To a lesser extent, past OC use was positively associated with PFASs (estimates ranged from 7.2-32.1%). Compared with never users, using OCs for 10 or more years was associated with increased PFAS concentrations, except for PFDA and PFUnDA (estimates for other PFASs ranged from 18.9-46.2%). We observed little effect of age at first OC use.

Conclusions: This analysis shows that characteristics of OC use, and duration of use in particular, may be important considerations when investigating relationships between women's reproductive outcomes and PFASs.
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http://dx.doi.org/10.1016/j.envint.2017.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899038PMC
March 2018

Multi-pathway human exposure assessment of phthalate esters and DINCH.

Environ Int 2018 03 19;112:115-126. Epub 2017 Dec 19.

Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address:

Phthalate esters are substances mainly used as plasticizers in various applications. Some have been restricted and phased out due to their adverse health effects and ubiquitous presence, leading to the introduction of alternative plasticizers, such as DINCH. Using a comprehensive dataset from a Norwegian study population, human exposure to DMP, DEP, DnBP, DiBP, BBzP, DEHP, DINP, DIDP, DPHP and DINCH was assessed by measuring their presence in external exposure media, allowing an estimation of the total intake, as well as the relative importance of different uptake pathways. Intake via different uptake routes, in particular inhalation, dermal absorption, and oral uptake was estimated and total intake based on all uptake pathways was compared to the calculated intake from biomonitoring data. Hand wipe results were used to determine dermal uptake and compared to other exposure sources such as air, dust and personal care products. Results showed that the calculated total intakes were similar, but slightly higher than those based on biomonitoring methods by 1.1 to 3 times (median), indicating a good understanding of important uptake pathways. The relative importance of different uptake pathways was comparable to other studies, where inhalation was important for lower molecular weight phthalates, and negligible for the higher molecular weight phthalates and DINCH. Dietary intake was the predominant exposure route for all analyzed substances. Dermal uptake based on hand wipes was much lower (median up to 2000 times) than the total dermal uptake via air, dust and personal care products. Still, dermal uptake is not a well-studied exposure pathway and several research gaps (e.g. absorption fractions) remain. Based on calculated intakes, the exposure for the Norwegian participants to the phthalates and DINCH was lower than health based limit values. Nevertheless, exposure to alternative plasticizers, such as DPHP and DINCH, is expected to increase in the future and continuous monitoring is required.
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http://dx.doi.org/10.1016/j.envint.2017.12.016DOI Listing
March 2018

Investigation of the Best Approach for Assessing Human Exposure to Poly- and Perfluoroalkyl Substances through Indoor Air.

Environ Sci Technol 2017 Nov 23;51(21):12836-12843. Epub 2017 Oct 23.

Department of Environmental Exposure and Epidemiology, Domain of Infection Control and Environmental Health, Norwegian Institute of Public Health , P.O. Box 4404 Nydalen, NO-0403 Oslo, Norway.

Per- and polyfluoroalkyl substances (PFASs), including fluorotelomer alcohols (FTOHs), perfluoroalkyl sulfonamidoethanols (FOSEs), and perfluoroalkyl sulfonamides (FOSAs), were assessed in 61 residential indoor air and 15 personal air samples collected in Oslo area, Norway. FTOHs were detected in all samples, and the median concentrations in residential indoor air were 2970, 10400, and 3120 pg m for 6:2, 8:2, and 10:2 FTOH, respectively. This is similar to or higher than previously reported in studies from the same geographical area and worldwide. FOSEs and FOSAs were detected in 49-70% and 7-13% of the residential indoor air samples, respectively. The median FTOH concentrations observed in personal air were 1970, 7170, and 1590 pg m for 6:2, 8:2, and 10:2 FTOH, respectively, which is 30 to 50% lower than the median concentrations in residential indoor air. No FOSEs or FOSAs were detected above the method detection limit (MDL) in the personal air samples. Intakes of perfluorohexanoate (PFHxA), perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), and perfluorooctyl sulfonate (PFOS) through inhalation and biotransformation of PFAS precursors in air were estimated. Median intakes of 1.7, 0.17, 5.7, 0.57, 1.8, 0.18, and 2.3 pg kg bw day were obtained in residential indoor air, while 1.0, 0.10, 3.3, 0.33, 0.88, and 0.09 pg kg bw day were found in personal air for PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, and PFOS, respectively. The median PFOA intakes from residential indoor air (5.7 pg kg bw day) and personal air (3.3 pg kg bw day) were both around 5 orders of magnitude lower than the tolerable daily intake (TDI) reported by the European Food Safety Authority (EFSA).
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http://dx.doi.org/10.1021/acs.est.7b03516DOI Listing
November 2017

Case Study on Screening Emerging Pollutants in Urine and Nails.

Environ Sci Technol 2017 04 22;51(7):4046-4053. Epub 2017 Mar 22.

Flemish Institute for Technological Research (VITO NV) , Boeretang 200, 2400 Mol, Belgium.

Alternative plasticizers and flame retardants (FRs) have been introduced as replacements for banned or restricted chemicals, but much is still unknown about their metabolism and occurrence in humans. We identified the metabolites formed in vitro for four alternative plasticizers (acetyltributyl citrate (ATBC), bis(2-propylheptyl) phthalate (DPHP), bis(2-ethylhexyl) terephthalate (DEHTP), bis(2-ethylhexyl) adipate (DEHA)), and one FR (2,2-bis (chloromethyl)-propane-1,3-diyltetrakis(2-chloroethyl) bisphosphate (V6)). Further, these compounds and their metabolites were investigated by LC/ESI-Orbitrap-MS in urine and finger nails collected from a Norwegian cohort. Primary and secondary ATBC metabolites had detection frequencies (% DF) in finger nails ranging from 46 to 95%. V6 was identified for the first time in finger nails, suggesting that this matrix may also indicate past exposure to FRs as well as alternative plasticizers. Two isomeric forms of DEHTP primary metabolite were highly detected in urine (97% DF) and identified in finger nails, while no DPHP metabolites were detected in vivo. Primary and secondary DEHA metabolites were identified in both matrices, and the relative proportion of the secondary metabolites was higher in urine than in finger nails; the opposite was observed for the primary metabolites. As many of the metabolites present in in vitro extracts were further identified in vivo in urine and finger nail samples, this suggests that in vitro assays can reliably mimic the in vivo processes. Finger nails may be a useful noninvasive matrix for human biomonitoring of specific organic contaminants, but further validation is needed.
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http://dx.doi.org/10.1021/acs.est.6b05661DOI Listing
April 2017

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

Environ Res 2016 Nov 25;151:80-90. Epub 2016 Jul 25.

VITO NV Flemish Institute for Technological Research, Boeretang 200, 2400 Mol, Belgium.

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.
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http://dx.doi.org/10.1016/j.envres.2016.07.025DOI Listing
November 2016

Exposure of Norwegian toddlers to perfluoroalkyl substances (PFAS): The association with breastfeeding and maternal PFAS concentrations.

Environ Int 2016 Sep 21;94:687-694. Epub 2016 Jul 21.

Domain of Infection Control and Environmental Health, Norwegian Institute of Public Health, Lovisenberggata 8, 0456 Oslo, Norway.

High exposure to perfluoroalkyl substances (PFASs) has been associated with adverse health effects in children. PFASs exposure pathways of toddlers might differ from those of infants and adults, and the investigations on determinants of PFASs exposure in early childhood are scarce. Our aims were to examine the PFAS blood concentrations in Norwegian toddlers and to assess their relationship with maternal PFAS concentrations in pregnancy and breastfeeding duration. We determined PFAS concentrations in 112 plasma samples of 3-year-old children collected at 2010-2011 and 99 maternal serum samples collected around delivery at 2007-2008. PFAS concentrations in children were regressed on duration of breastfeeding, and the effect modification by maternal prenatal PFAS concentrations was examined in 55 mother-child pairs. Six PFASs were quantifiable in >50% of both maternal and children samples. Positive and significant correlations ranging between 0.50 and 0.66 were found between maternal and child concentrations of the same PFAS congeners. Nevertheless, toddlers had higher total PFAS blood concentrations than their mothers, due to higher concentrations of PFOA, PFNA and PFHxS. Every month of breastfeeding was associated with an increase of 3.3% (95% Confidence Intervals (CI): 0.8-5.8) for PFOS, 4.7% (95%CI: 2.8-6.6) for PFOA and 6.1% (95% CI: 2.6-9.7) for PFHpS in toddlers' plasma and a dose-response association was found, after adjustment for confounders. However, PFNA and PFUnDA concentrations in children were not associated with either maternal concentrations or breastfeeding duration. Our findings suggest that transplacental transfer, prenatally, and breastfeeding, postanatally, are among the main determinants of PFOS, PFOA, PFHxS and PFHpS concentrations in toddlers, while that was not the case for PFNA and PFUnDA. Nevertheless, due to the small number of mother child-pairs in our study, our results should be interpreted with caution.
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http://dx.doi.org/10.1016/j.envint.2016.07.006DOI Listing
September 2016

Brief Report: Plasma Concentrations of Perfluorooctane Sulfonamide and Time-to-pregnancy Among Primiparous Women.

Epidemiology 2016 09;27(5):712-5

From the aDepartment of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health at Houston, San Antonio Regional Campus, San Antonio, TX; bSouthwest Center for Occupational and Environmental Health, The University of Texas School of Public Health at Houston, Houston, TX; cNorwegian Institute of Public Health, Oslo, Norway; dDepartment of Health and Human Services, National Institute for Environmental Health Sciences, National Institutes of Health, Durham NC.

Background: A previous study reported a negative association between perfluorooctane sulfonamide (PFOSA) concentrations and fecundability.

Methods: We examined this association among women enrolled in the Norwegian Mother and Child Cohort Study (MoBa), in 2003-2004. This analysis was restricted to 451 primiparous women to avoid bias due to previous pregnancy. Self-reported time-to-pregnancy (TTP) and plasma were obtained around 18 weeks of gestation. Approximately half of the women had measurable PFOSA levels; missing values were multiply imputed. We used the logistic analogue of discrete-time survival analysis to examine the adjusted association between PFOSA, other perfluoroalkyl substances, and TTP.

Results: The median-measured PFOSA concentration was 0.03 ng/ml (interquartile range = 0.02, 0.07). The age and body mass index-adjusted association between an interquartile distance increase in PFOSA and TTP was 0.91 (95% confidence interval = 0.71, 1.17). Imputation of missing PFOSA resulted in similar estimates. No association was observed with other perfluoroalkyl substances.

Conclusion: Based on a weakly decreased fecundability odds ratio, we found only limited support for an association between plasma PFOSA concentrations and TTP among primiparous women. See Video Abstract at http://links.lww.com/EDE/B79.
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http://dx.doi.org/10.1097/EDE.0000000000000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387409PMC
September 2016

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

Environ Res 2015 Jul 15;140:421-9. Epub 2015 May 15.

Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, DHHS, 111 T.W. Alexander Drive, Research Triangle Park, NC, USA.

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.
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http://dx.doi.org/10.1016/j.envres.2015.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492849PMC
July 2015

Cord blood gene expression supports that prenatal exposure to perfluoroalkyl substances causes depressed immune functionality in early childhood.

J Immunotoxicol 2016 27;13(2):173-80. Epub 2015 Mar 27.

c Division of Environmental Medicine , Norwegian Institute of Public Health (NIPH) , Oslo , Norway.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a class of synthetic compounds that have widespread use in consumer and industrial applications. PFAS are considered environmental pollutants that have various toxic properties, including effects on the immune system. Recent human studies indicate that prenatal exposure to PFAS leads to suppressed immune responses in early childhood. In this study, data from the Norwegian BraMat cohort was used to investigate transcriptomics profiles in neonatal cord blood and their association with maternal PFAS exposure, anti-rubella antibody levels at 3 years of age and the number of common cold episodes until 3 years. Genes associated with PFAS exposure showed enrichment for immunological and developmental functions. The analyses identified a toxicogenomics profile of 52 PFAS exposure-associated genes that were in common with genes associated with rubella titers and/or common cold episodes. This gene set contains several immunomodulatory genes (CYTL1, IL27) as well as other immune-associated genes (e.g. EMR4P, SHC4, ADORA2A). In addition, this study identified PPARD as a PFAS toxicogenomics marker. These markers can serve as the basis for further mechanistic or epidemiological studies. This study provides a transcriptomics connection between prenatal PFAS exposure and impaired immune function in early childhood and supports current views on PPAR- and NF-κB-mediated modes of action. The findings add to the available evidence that PFAS exposure is immunotoxic in humans and support regulatory policies to phase out these substances.
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http://dx.doi.org/10.3109/1547691X.2015.1029147DOI Listing
September 2016

Perfluoroalkyl substances during pregnancy and validated preeclampsia among nulliparous women in the Norwegian Mother and Child Cohort Study.

Am J Epidemiol 2014 Apr 20;179(7):824-33. Epub 2014 Feb 20.

Perfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants, and human exposure to these substances may be related to preeclampsia, a common pregnancy complication. Previous studies have found serum concentrations of PFAS to be positively associated with pregnancy-induced hypertension and preeclampsia in a population with high levels of exposure to perfluorooctanoate. Whether this association exists among pregnant women with background levels of PFAS exposure is unknown. Using data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health, we carried out a study of nulliparous pregnant women enrolled in 2003-2007 (466 cases, 510 noncases) to estimate associations between PFAS concentrations and an independently validated diagnosis of preeclampsia. We measured levels of 9 PFAS in maternal plasma extracted midpregnancy; statistical analyses were restricted to 7 PFAS that were quantifiable in more than 50% of samples. In proportional hazards models adjusted for maternal age, prepregnancy body mass index (weight (kg)/height (m)(2)), educational level, and smoking status, we observed no strongly positive associations between PFAS levels and preeclampsia. We found an inverse association between preeclampsia and the highest quartile of perfluoroundecanoic acid concentration relative to the lowest quartile (hazard ratio = 0.55, 95% confidence interval: 0.38, 0.81). Overall, our findings do not support an increased risk of preeclampsia among nulliparous Norwegian women with background levels of PFAS exposure.
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http://dx.doi.org/10.1093/aje/kwt432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969534PMC
April 2014

Association between perfluoroalkyl substances and thyroid stimulating hormone among pregnant women: a cross-sectional study.

Environ Health 2013 Sep 8;12(1):76. Epub 2013 Sep 8.

Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA.

Background: Perfluoroalkyl substances (PFASs) are a group of highly persistent chemicals that are widespread contaminants in wildlife and humans. Exposure to PFAS affects thyroid homeostasis in experimental animals and possibly in humans. The objective of this study was to examine the association between plasma concentrations of PFASs and thyroid stimulating hormone (TSH) among pregnant women.

Methods: A total of 903 pregnant women who enrolled in the Norwegian Mother and Child Cohort Study from 2003 to 2004 were studied. Concentrations of thirteen PFASs and TSH were measured in plasma samples collected around the 18th week of gestation. Linear regression models were used to evaluate associations between PFASs and TSH.

Results: Among the thirteen PFASs, seven were detected in more than 60% of samples and perfluorooctane sulfonate (PFOS) had the highest concentrations (median, 12.8 ng/mL; inter-quartile range [IQR], 10.1 -16.5 ng/mL). The median TSH concentration was 3.5 (IQR, 2.4 - 4.8) μIU/mL. Pregnant women with higher PFOS had higher TSH levels. After adjustment, with each 1 ng/mL increase in PFOS concentration, there was a 0.8% (95% confidence interval: 0.1%, 1.6%) rise in TSH. The odds ratio of having an abnormally high TSH, however, was not increased, and other PFASs were unrelated to TSH.

Conclusions: Our results suggest an association between PFOS and TSH in pregnant women that is small and may be of no clinical significance.
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http://dx.doi.org/10.1186/1476-069X-12-76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847507PMC
September 2013

Pre-natal exposure to perfluoroalkyl substances may be associated with altered vaccine antibody levels and immune-related health outcomes in early childhood.

J Immunotoxicol 2013 Oct-Dec;10(4):373-9. Epub 2013 Jan 25.

Division of Environmental Medicine, Norwegian Institute of Public Health , Oslo , Norway.

Perfluoroalkyl substances (PFAS) are suggested to have immunosuppressive effects; exposure in utero and in the first years of life is of special concern as fetuses and small children are highly vulnerable to toxicant exposure. The objective of this study was to investigate the effect of pre-natal exposure to PFAS on responses to pediatric vaccines and immune-related health outcomes in children up to 3 years of age. In the prospective birth-cohort BraMat, a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa), pregnant women from Oslo and Akershus, Norway, were recruited during 2007-2008. Three annual questionnaire-based follow-ups were performed. Blood samples were collected from the mothers at the time of delivery and from the children at the age of 3 years. As a measure of pre-natal exposure to PFAS, the concentrations of perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) were determined in maternal blood from 99 BraMat participants. Main outcome measures were anti-vaccine antibody levels, common infectious diseases and allergy- and asthma-related health outcomes in the children up to the age of 3 years. There was an inverse association between the level of anti-rubella antibodies in the children's serum at age 3 years and the concentrations of the four PFAS. Furthermore, there was a positive association between the maternal concentrations of PFOA and PFNA and the number of episodes of common cold for the children, and between PFOA and PFHxS and the number of episodes of gastroenteritis. No associations were found between maternal PFAS concentrations and the allergy- and asthma-related health outcomes investigated. The results indicate that pre-natal exposure to PFAS may be associated with immunosuppression in early childhood.
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http://dx.doi.org/10.3109/1547691X.2012.755580DOI Listing
July 2014

Perfluorinated compounds in relation to birth weight in the Norwegian Mother and Child Cohort Study.

Am J Epidemiol 2012 Jun 19;175(12):1209-16. Epub 2012 Apr 19.

National Institute for Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Durham, North Carolina, USA.

Perfluorooctane sulfonate and perfluorooctanoic acid are perfluorinated compounds (PFCs) widely distributed in the environment. Previous studies of PFCs and birth weight are equivocal. The authors examined this association in the Norwegian Mother and Child Cohort Study (MoBa), using data from 901 women enrolled from 2003 to 2004 and selected for a prior case-based study of PFCs and subfecundity. Maternal plasma samples were obtained around 17 weeks of gestation. Outcomes included birth weight z scores, preterm birth, small for gestational age, and large for gestational age. The adjusted birth weight z scores were slightly lower among infants born to mothers in the highest quartiles of PFCs compared with infants born to mothers in the lowest quartiles: for perfluorooctane sulfonate, β = -0.18 (95% confidence interval: -0.41, 0.05) and, for perfluorooctanoic acid, β = -0.21 (95% confidence interval: -0.45, 0.04). No clear evidence of an association with small for gestational age or large for gestational age was observed. Perfluorooctane sulfonate and perfluorooctanoic acid were each associated with decreased adjusted odds of preterm birth, although the cell counts were small. Whether some of the associations suggested by these findings may be due to a noncausal pharmacokinetic mechanism remains unclear.
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http://dx.doi.org/10.1093/aje/kwr459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372312PMC
June 2012

Perfluorinated compounds and subfecundity in pregnant women.

Epidemiology 2012 Mar;23(2):257-63

Department of Health and Human Services, National Institute for Environmental Health Sciences, National Institutes of Health, Durham, NC 27709, USA.

Background: Perfluorinated compounds are ubiquitous pollutants; epidemiologic data suggest they may be associated with adverse health outcomes, including subfecundity. We examined subfecundity in relation to 2 perfluorinated compounds-perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA).

Methods: This case-control analysis included 910 women enrolled in the Norwegian Mother and Child Cohort Study in 2003 and 2004. Around gestational week 17, women reported their time to pregnancy and provided blood samples. Cases consisted of 416 women with a time to pregnancy greater than 12 months, considered subfecund. Plasma concentrations of perfluorinated compounds were analyzed using liquid chromatography-mass spectrometry. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each pollutant quartile using logistic regression. Estimates were further stratified by parity.

Results: The median plasma concentration of PFOS was 13.0 ng/mL (interquartile range [IQR] = 10.3-16.6 ng/mL) and of PFOA was 2.2 ng/mL (IQR = 1.7-3.0 ng/mL). The relative odds of subfecundity among parous women was 2.1 (95% CI = 1.2-3.8) for the highest PFOS quartile and 2.1 (1.0-4.0) for the highest PFOA quartile. Among nulliparous women, the respective relative odds were 0.7 (0.4-1.3) and 0.5 (0.2-1.2).

Conclusion: Previous studies suggest that the body burden of perfluorinated compounds decreases during pregnancy and lactation through transfer to the fetus and to breast milk. Afterward, the body burden may increase again. Among parous women, increased body burden may be due to a long interpregnancy interval rather than the cause of a long time to pregnancy. Therefore, data from nulliparous women may be more informative regarding toxic effects of perfluorinated compounds. Our results among nulliparous women did not support an association with subfecundity.
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http://dx.doi.org/10.1097/EDE.0b013e31823b5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276687PMC
March 2012
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