Early-life exposure to perfluoroalkyl substances and serum antibody concentrations towards common childhood vaccines in 18-month-old children in the Odense Child Cohort.

Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with reduced antibody response to childhood vaccinations. Previous studies have mostly focused on antibodies against diphtheria or tetanus, while fewer studies have assessed antibodies toward attenuated viruses, such as measles, mumps or rubella (MMR). Therefore, we set out to determine associations between prenatal and early postnatal PFAS exposure and vaccine-specific Immunoglobulin G (IgG) in the background-exposed Odense Child Cohort. Blood samples were drawn in pregnancy at gestation weeks 8-16 and from the offspring at age 18 months. In the maternal serum samples we quantified perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA). In the offspring serum samples we quantified the same five PFAS compounds and IgG towards diphtheria, tetanus and MMR. A total of 880 and 841 children were included in the analyses of diphtheria and tetanus or MMR, respectively. Multiple linear regression models were used for estimation of difference in virus-specific IgG per doubling of PFAS concentrations. Maternal PFAS concentrations were non-significantly inversely associated with most vaccine-specific antibody concentrations. Likewise, child PFAS concentrations were associated with non-significant reductions of antibodies towards tetanus and MMR. A significant reduction in the percent difference in mumps antibody concentration per doubling of child PFNA (-9.2% (95% confidence interval: -17.4;-0.2)), PFHxS (-8.3% (-15.0;-1.0) and PFOS (-7.9% (-14.8;-0.4) was found. These findings are of public health concern, as inadequate response towards childhood vaccines may represent a more general immune dysfunction.

Concentrations of tetanus and diphtheria antibodies in vaccinated Greenlandic children aged 7-12 years exposed to marine pollutants, a cross sectional study.

Previous studies have shown immunotoxic effects of environmental chemicals, and the European Food Safety Authority (EFSA) recently identified a need for more studies on PFAS immunotoxicity in different populations. In the Arctic, populations are exposed to several environmental chemicals through marine diet, and the objective of this study was therefore to examine the association between Greenlandic children's exposure to major environmental chemicals and their concentrations of diphtheria and tetanus vaccine antibodies after vaccination. The study includes cross-sectional data from Greenlandic children aged 7-12 years examined during 2012-2015. A total of 338 children were eligible for the study, and 175 of these had available vaccination records. A parent or guardian participated in a structured interview, and a blood sample from the child was analyzed for specific antibodies against diphtheria and tetanus as well as perfluoroalkyl substances (PFASs), polychlorinated biphenyls (PCBs) and total mercury. Furthermore, for a subgroup, blood samples from pregnancy were available and analyzed for environmental contaminants. The associations between the environmental exposures and antibody concentrations and odds of having antibody concentrations below the protective level were examined in linear and logistic regression models. In crude analyses, elevated concentrations of some of the contaminants were associated with higher concentrations of diphtheria and tetanus antibodies, but the associations were reversed when adjusting for area of residence, and duration of being breastfed and including children with a known vaccination date only. Each 1 ng/mL increase in serum concentrations of perfluorohexane sulfonic acid (PFHxS) and perfluorooctane sulfonic acid (PFOS) was associated with decreases of 78 % (95 % CI: 25-94 %) and 9 % (95 % CI: 2-16 %), respectively, in diphtheria antibody concentrations. Exposure to PCBs and all PFASs was associated with markedly increased odds of having diphtheria antibody concentrations below the protective level. For each 1 ng/mL increase in serum concentrations of PFHxS, PFOS, perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), odds of not having protective levels of diphtheria antibodies were increased 6.44 times (95 % CI: 1.51-27.36), 1.14 times (95 % CI: 1.04-1.26), 1.96 times (95 % CI: 1.07-3.60), and 5.08 times (95 % CI: 1.32-19.51, respectively. No consistent associations were seen between maternal contaminant concentrations and vaccine antibody concentrations. In conclusion, we found that increased exposure to environmental chemicals among children in this Arctic population were associated with a decrease in post-vaccination antibody concentrations and with increased odds of not being protected against diphtheria despite appropriate vaccination. These findings emphasize the risk of environmental chemical exposures also in this Arctic population.

Pregnancy exposure to bisphenol A and duration of breastfeeding.

INTRODUCTION: Bisphenol A (BPA) is frequently used in the production of plastics. It is an endocrine disruptor, and BPA exposure in mice has been associated with reduced offspring growth due to insufficient milk production. However, human studies of associations between BPA exposure and duration of breastfeeding are sparse. METHODS: Pregnant women from the Odense Child Cohort (n = 725) donated a third trimester morning urine sample, which was analyzed for BPA by LC-MS/MS. Information about duration of exclusive and any breastfeeding was obtained through questionnaires three and 18 months postpartum, and a subgroup of women responded to weekly text messages about breastfeeding. Associations between pregnancy BPA exposure and duration of breastfeeding were analyzed using Cox regression adjusting for potential confounders. RESULTS: The median urine BPA concentration was 1.29 ng/mL. Compared to women within the lowest tertile of BPA exposure, women in the second and third tertile were slightly more likely to terminate breastfeeding at any given time; HRs (95% CI) were 1.05 (0.87; 1.26) and 1.06 (0.89; 1.27), respectively, and to terminate exclusive breastfeeding at any time up to 20 weeks after birth, HRs (95% CI) were 1.07 (0.88; 1.28) and 1.06 (0.88; 1.27), respectively. However, confidence intervals were also compatible with no effect or even a protective effect. DISCUSSION: This study indicated that high BPA exposure in pregnancy was associated with shorter duration of breastfeeding. Although our findings were not statistically significant, all estimates were above one suggesting increased risk of early breastfeeding termination with high exposure. Using a single spot morning urine sample to measure BPA has likely caused imprecision as it might not adequately reflect long term exposure. Future studies should consider measuring BPA more than once, including other timepoints during pregnancy and after birth.

Higher free thyroxine associated with PFAS exposure in first trimester. The Odense Child Cohort.

BACKGROUND: Perfluoroalkyl substances (PFAS) are endocrine disrupting chemicals with elimination half-lives ranging from four to eight years. Experimental studies found PFAS able to interfere with thyroid hormone-binding proteins. During the first 20 weeks of gestation (GW), the fetus is reliant on placental transfer of maternal thyroid hormones, mainly free thyroxine (FT4). However, previous studies investigating associations between exposure to PFAS and thyroid hormone status mainly focused on blood samples from late pregnancy or umbilical cord with mixed findings. OBJECTIVES: To investigate associations between serum-PFAS concentrations and thyroid hormone status in early pregnancy as reflected by FT4 and thyroid-stimulating hormone (TSH). METHODS: In the Odense Child Cohort, a single-center study, we measured maternal pregnancy serum concentrations of five PFAS: perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA); and FT4 and TSH in 1048 pregnant women at median GW 12 (25th, 75th percentile: 10, 15). Multivariate linear regression models were performed to estimate associations between PFAS exposure and thyroid hormone status. RESULTS: A doubling in PFOS, PFOA, and PFNA concentrations was associated with an increment in FT4 concentration by 1.85% (95% CI: 0.66%, 3.05%), 1.29% (95% CI: 0.21%, 2.39%), and 1.70% (95% CI: 0.48%, 2.94%), respectively, in adjusted analyses. A statistically significant dose-response relationship was observed across exposure quartiles for PFOS, PFOA, and PFNA in the association with FT4. No association was found between concentrations of PFAS and TSH in adjusted analyses. CONCLUSION: Exposure to PFOS, PFOA, and PFNA was associated with higher FT4 concentrations in women during early pregnancy. The potential clinical implications of these findings remain to be clarified.

Prenatal exposure to bisphenol A and autistic- and ADHD-related symptoms in children aged 2 and5 years from the Odense Child Cohort.

BACKGROUND: Bisphenol A (BPA) is a non-persistent chemical with endocrine disrupting abilities used in a variety of consumer products. Fetal exposure to BPA is of concern due to the elevated sensitivity, which particularly relates to the developing brain. Several epidemiological studies have investigated the association between prenatal BPA exposure and neurodevelopment, but the results have been inconclusive. OBJECTIVE: To assess the association between in utero exposure to BPA and Attention Deficit/Hyperactivity Disorder (ADHD-) symptoms and symptoms of Autism Spectrum Disorder (ASD) in 2 and 5-year old Danish children. METHOD: In the prospective Odense Child Cohort, BPA was measured in urine samples collected in gestational week 28 and adjusted for osmolality. ADHD and ASD symptoms were assessed with the use of the ADHD scale and ASD scale, respectively, derived from the Child Behaviour Checklist preschool version (CBCL/1½-5) at ages 2 and 5 years. Negative binomial and multiple logistic regression analyses were performed to investigate the association between maternal BPA exposure (continuous ln-transformed or divided into tertiles) and the relative differences in ADHD and ASD problem scores and the odds (OR) of an ADHD and autism score above the 75th percentile adjusting for maternal educational level, maternal age, pre-pregnancy BMI, parity and child age at evaluation in 658 mother-child pairs at 2 years of age for ASD-score, and 427 mother-child pairs at 5 years of age for ADHD and ASD-score. RESULTS: BPA was detected in 85.3% of maternal urine samples even though the exposure level was low (median 1.2 ng/mL). No associations between maternal BPA exposure and ASD at age 2 years or ADHD at age 5 years were found. Trends of elevated Odds Ratios (ORs) were seen among 5 year old children within the 3rd tertile of BPA exposure with an ASD-score above the 75th percentile (OR = 1.80, 95% CI 0.97,3.32), being stronger for girls (OR = 3.17, 95% CI 1.85,9.28). A dose-response relationship was observed between BPA exposure and ASD-score at 5 years of age (p-trend 0.06) in both boys and girls, but only significant in girls (p-trend 0.03). CONCLUSION: Our findings suggest that prenatal BPA exposure even in low concentrations may increase the risk of ASD symptoms which may predict later social abilities. It is therefore important to follow-up these children at older ages, measure their own BPA exposure, and determine if the observed associations persist.

Maternal phthalate exposure and asthma, rhinitis and eczema in 552 children aged 5 years; a prospective cohort study.

BACKGROUND: Prenatal phthalate exposure has been suggested to alter immune responses and increase the risk of asthma, eczema and rhinitis. However, few studies have examined the effects in prospective cohorts and only one examined rhinitis. We therefore studied associations between maternal urinary concentrations of phthalate metabolites and asthma, eczema and rhinitis in offspring aged 5 years. METHODS: From 552 pregnant women in the Odense Child Cohort, we quantified urinary concentrations of 12 phthalate metabolites in third trimester. We assessed asthma, rhinitis and eczema in their offspring at age 5 years with a questionnaire based on the International Study of Asthma and Allergies in Childhood (ISAAC), and conducted logistic regression adjusting for relevant confounders. RESULTS: 7.4% of the children had asthma, 11.7% eczema and 9.2% rhinitis. Phthalate exposure was low compared to previous cohorts. No significant associations between prenatal phthalate exposure and asthma were found. Odds ratios (ORs) of child rhinitis with a doubling in ΣDiNPm and di-2-ethylhexyl phthalate metabolite (ΣDEHPm) concentrations were, respectively, 1.15 (95% confidence interval (CI) 0.97,1.36) and 1.21 (CI 0.93,1.58). The OR of eczema when doubling ΣDiNPm was 1.24 (CI 1.00,1.55), whereas the OR of using medicine against eczema when doubling a di-ethyl phthalate (DEP) metabolite was 0.81 (CI 0.68,0.96). CONCLUSION: The lack of association between maternal phthalate exposure and asthma in the offspring may be due to low exposure and difficulties in determining asthma in 5-year-olds. The higher odds of rhinitis may raise public concern but further research in larger cohorts of older children is warranted.

Association between prenatal exposure to perfluoroalkyl substances and asthma in 5-year-old children in the Odense Child Cohort.

BACKGROUND: Asthma is the most common non-communicable disease in children. Prenatal exposure to perfluoroalkyl substances (PFASs), a group of persistent environmental chemicals with endocrine disrupting abilities, has been associated with immunomodulation and may contribute to the aetiology of asthma. We investigated the associations between prenatal exposure to five PFASs and asthma in 5-year-old children. METHODS: We studied 981 mother-child pairs within the Odense Child Cohort (OCC), Denmark. We measured perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) in maternal serum donated in early pregnancy. A standardized questionnaire based on the International Study of Asthma and Allergies in Childhood (ISAAC) was used to assess wheeze, self-reported asthma and doctor-diagnosed asthma among children at age 5 years. Associations were examined using logistic regression analyses adjusting for parity, maternal educational level, maternal pre-pregnancy BMI, asthma predisposition and child sex. RESULTS: Among the 5-year-old children 18.6% reported wheeze and 7.1% reported asthma. We found no association between prenatal exposure to PFAS and doctor-diagnosed asthma or wheeze. Prenatal PFAS exposure was associated with self-reported asthma, although only significant for PFNA (OR = 1.84, 95% CI 1.03,3.23). CONCLUSION: Our findings support the suggested immunomodulatory effects of PFASs, however, additional studies are warranted. In order to verify our findings, it is important to re-examine the children with postnatal measurements of serum PFAS concentrations and additional clinical diagnostic testing at an older age where an asthma diagnosis is more valid.

Tuberculin reaction and BCG scar: association with infant mortality.

OBJECTIVE: To test the hypothesis that having a scar and a positive tuberculin skin test (TST) response after vaccination with Bacille Calmette-Guérin (BCG) is associated with reduced infant mortality. METHODS: We studied cohorts of 2709 normal-birthweight (NBW) and 1102 low-birthweight (LBW) infants in Guinea-Bissau. Children were enrolled in randomised trials between year 2002 and 2008 and received BCG vaccination at birth. BCG scars and TST responses were assessed at 2 and 6 months of age. The infants were followed for mortality to 12 months of age, and survival was analysed using Cox regression. RESULTS: At age 2 months, 88% of NBW children and 91% of LBW children had a BCG scar, and 36% and 17% had a TST response, respectively. The LBW infants had nearly twofold higher mortality (4.5%) than the NBW infants (2.8%) between 2 and 12 months of age. In the LBW cohort, the adjusted mortality rate ratio (MRR) comparing children with a BCG scar with those without was 0.42 (95% CI = 0.19; 0.93). There was a similar tendency for TST positivity: MRR = 0.47 (95% CI = 0.14; 1.54). For LBW children who had both a positive TST reaction and a scar, the MRR was 0.22 (95% CI = 0.05; 0.87). For NBW children, a scar and a positive TST were associated with 20% reductions in mortality, which did not reach statistical significance. CONCLUSION: We confirmed previous observations that having a scar and a TST response after BCG vaccination is associated with lower mortality risk. The possibility of revaccinating scar-negative children should be considered.

Asthma and allergy in children with and without prior measles, mumps, and rubella vaccination.

BACKGROUND: The existing literature on the association between measles vaccination and subsequent risk of allergic disease is inconclusive. The aim of this study was, therefore, to determine whether measles, mumps, and rubella (MMR) vaccination administered in early childhood was associated with asthma and allergic diseases at ages 5, 7 and 13 yrs in a birth cohort. METHODS: In the Faroe Islands, 640 children were followed from birth. Follow-up examinations at ages 5, 7 and 13 yrs included a physical examination and a maternal questionnaire about the child's health. At age 7, total and grass-specific IgE was quantified in the child's serum, and at age 13, the children underwent skin prick tests (SPT). The child's vaccination card was reviewed at examinations. RESULTS: At age 5, 533 of 555 children had been vaccinated for MMR. After confounder adjustment, we found early life MMR vaccination to be associated with a two-third reduction in the odds of asthma (OR: 0.33, 95% CI: 0.12; 0.90) and hypersensitivity/allergy (OR: 0.32, 95% CI: 0.11; 0.88) at age 5, and the substantially decreased odds of asthma were replicated at age 13 (OR: 0.22, 95% CI: 0.08; 0.56). At age 7, serum total IgE was reduced by 62.8% (CI 95%: -84.3%; -11.9%) in the vaccinated children. MMR vaccination was not significantly associated with allergic rhinoconjuctivitis symptoms, eczema, or SPT reactions at age 13. CONCLUSIONS: MMR vaccination early in life may have a protective effect against allergy at least up to age 7 and against asthma through age 13 yrs.

Pregnancy Exposure to Perfluoroalkyl Substances and Associations With Prolactin Concentrations and Breastfeeding in the Odense Child Cohort.

CONTEXT: Human exposure to perfluoroalkyl substances (PFAS) has been associated with reduced duration of breastfeeding, although not consistently so, and mechanisms by which PFAS might affect breastfeeding are unknown. OBJECTIVE: To examine the association between early pregnancy serum-PFAS concentrations and breastfeeding termination and to elucidate the potential role of serum-prolactin concentrations in pregnancy. MATERIALS AND METHODS: Pregnant women from the Odense Child Cohort provided blood samples for analysis of 5 major PFAS (n = 1300) and prolactin concentrations (n = 924). They subsequently provided information about the duration of breastfeeding in questionnaires at 3 and 18 months postpartum, and a subgroup also provided breastfeeding information via weekly cell phone text messages. Associations between serum-PFAS concentrations and breastfeeding termination were analyzed using Cox regressions, while linear regression was used to assess associations between serum-PFAS and prolactin concentrations. RESULTS: Increased serum concentrations of perfluorooctane sulfonic acid, perfluorooctanoic acid, perfluorononanoic acid, and ∑PFAS were associated with a 16% (95% CI: 4%-30%), 14% (95% CI: 2%-26%), 14% (95% CI: 3%-27%), and 20% (95% CI: 6%-36%), respectively, increased risk of terminating breastfeeding at any given time after childbirth. Serum-PFAS concentrations were not associated with serum-prolactin concentrations. CONCLUSIONS: These findings are of public health importance due to the global exposures to PFAS. Because breastfeeding is crucial to promote both child health and maternal health, adverse PFAS effects on the ability to breastfeed may have long-term health consequences.

A Review of Dietary Intake of Acrylamide in Humans.

The dietary intake of acrylamide (AA) is a health concern, and food is being monitored worldwide, but the extent of AA exposure from the diet is uncertain. The aim of this review was to provide an overview of estimated dietary intake. We performed a PubMed search identifying studies that used dietary questionnaires and recalls to estimate total dietary AA intake. A total of 101 studies were included, corresponding to 68 original study populations from 26 countries. Questionnaires were used in 57 studies, dietary recalls were used in 33 studies, and 11 studies used both methods. The estimated median AA intake ranged from 0.02 to 1.53 µg/kg body weight/day between studies. Children were represented in 25 studies, and the body-weight-adjusted estimated AA intake was up to three times higher for children than adults. The majority of studies were from Europe (n = 65), Asia (n = 17), and the USA (n = 12). Studies from Asia generally estimated lower intakes than studies from Europe and the USA. Differences in methods undermine direct comparison across studies. The assessment of AA intake through dietary questionnaires and recalls has limitations. The integration of these methods with the analysis of validated biomarkers of exposure/internal dose would improve the accuracy of dietary AA intake exposure estimation. This overview shows that AA exposure is widespread and the large variation across and within populations shows a potential for reduced intake among those with the highest exposure.

Neonatal Bacille Calmette-Guérin vaccination and tuberculin skin test reactions at 2- and 6-months: Effects on mortality up to 1 year of age.

BACKGROUND: In randomized trials, Bacille Calmette-Guérin (BCG) vaccine has been associated with reduced all-cause mortality. BCG-induced Tuberculin Skin Test (TST) reactions have also been associated with reduced all-cause mortality. We aimed to assess the association between TST responses and subsequent mortality in three birth cohorts and conducted a meta-analysis of existing studies. METHODS: Observational study within three Guinea-Bissau BCG trial birth cohorts (conducted 2002-04, 2009-2013 and 2014-18) that encompassed children who were BCG-vaccinated within 28 days with TSTs performed at 2- (n = 1389) and 6-months (n = 2635) of age. We evaluated TST reaction determinants by binomial regression and assessed the association between TSTs > 1 mm (reactors) vs. ≤ 1 mm (non-reactors) and subsequent mortality risk up to age 12 months in Cox-models providing Mortality Rate Ratios (MRRs). We searched PubMed for studies to calculate meta-estimates of the association between TST reactivity by age 2- and 6-months and all-cause mortality. RESULTS: Large post-vaccination wheal size was associated with 6-month TST positivity and so was receiving BCG-Denmark or BCG-Japan, compared with BCG-Russia. By age 2 months, 22% (302/1389) of infants were TST reactors with a 2-12-month mortality risk of 1.7% (5/302) vs. 3.3% (36/1087) for non-reactors, the corresponding reactor/non-reactor MRR = 0.49 (0.19-1.26). By age 6 months, 44% (1149/2635) of infants were reactors and the 6-12-month mortality risk was 0.4% (4/1149) vs. 0.6% (9/1486) for non-reactors, the MRR = 0.87 (0.27-2.86). The literature search provided 3 studies. The meta-analysis revealed a uniform pattern of reduced mortality associated with TST reactivity, a TST response by 2 months being associated with an MRR of 0.59 (0.39-0.90); for 6-month TST responses the MRR was 0.65 (0.43-1.00). CONCLUSION: Among BCG-vaccinated infants, TST reactions were associated with markedly reduced mortality. Improved vaccination technique and using certain BCG strains could lead to a higher TST reaction prevalence, which would enhance BCG's beneficial non-specific effects.

Prenatal exposure to pyrethroid and organophosphate insecticides and language development at age 20-36 months among children in the Odense Child Cohort.

BACKGROUND: Prenatal exposure to organophosphate and pyrethroid insecticides has been associated with impaired neurodevelopment. Few longitudinal studies have investigated associations with early language development in populations with mainly low dietary exposure. OBJECTIVE: To investigate associations between biomarkers of maternal gestational exposure to organophosphate and pyrethroid insecticides and the child's language development at age 20-36 months in the prospective Odense Child Cohort. METHODS: Metabolites of organophosphate and pyrethroid insecticides were measured in maternal urine samples collected at gestational week 28. Language development was assessed among 755 singletons at age 20-36 months using the Vocabulary and Complexity scores of the MacArthur-Bates Communicative Development Inventories, standardized into age and sex specific percentile scores according to a Danish reference study. Multiple logistic regression models were used to estimate the odds of scoring below the 15th percentile scores in relation to maternal urinary insecticide metabolite concentrations after adjustment for confounders. RESULTS: The generic pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA) and the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPY) were detectable in more than 90% of the urine samples analyzed. Likewise, 82.2% had detectable concentrations of diethyl phosphates (DE) and 58.4% of dimethyl phosphates (DM), both of which are common metabolites of organophosphate insecticides. None of the metabolites was associated with higher odds of delayed results below the 15th percentile language scores. In contrast, reduced probability for scoring below the 15th percentile Vocabulary score was seen for the highest tertile of 3-PBA in boys and for the upper tertile of TCPY and DE in girls. CONCLUSION: In this prospective cohort, with predominantly dietary insecticide exposure, we found no evidence that gestational exposure to organophosphate or pyrethroid insecticides adversely affected early language development in the children. The observed indication of a positive effect of insecticides on language development may be explained by residual and unmeasured confounding from socioeconomic factors and dietary habits. Follow-up of these children should include assessment of more complex cognitive functions in later childhood, as well as associations with their own postnatal insecticide exposure.

Exposure to perfluoroalkyl substances during fetal life and hospitalization for infectious disease in childhood: A study among 1,503 children from the Odense Child Cohort.

INTRODUCTION: The immunosuppressive properties of PFASs are widely recognized. Early-life exposure to PFAS has been linked to reduced immune response to childhood vaccinations and increased rates of common infectious diseases, but implications for hospitalizations are unclear. OBJECTIVES: To investigate the association between maternal serum concentrations of five PFASs during pregnancy and the child's rate of hospitalization due to common infectious diseases between birth and 4 years of age. METHODS: Serum samples from first trimester pregnant women from the Odense Child Cohort (OCC) collected in 2010-2012 were analyzed for concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and three other PFASs. Data on child hospitalizations with an ICD-10 code for infectious disease was obtained from the Danish National Patient Register. The following were identified: upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), gastrointestinal infections (GI), and other infections. The Andersen-Gill Cox proportional hazard model for recurrent events was used to investigate the association between PFAS exposure and hospitalizations. The resulting estimates were hazard ratios (HRs), which express the relative change in the instantaneous risk of hospitalization with a doubling in maternal PFAS concentration. RESULTS: A total of 1,503 mother-child pairs were included, and 26% of the children were hospitalized at least once for infectious disease. A doubling in maternal PFOS concentration was associated with a 23% increase in the risk of hospitalization due to any infection (HR: 1.23 (95% CI: 1.05, 1.44). There was indication of an interaction between child sex and PFOS (p = 0.07) and PFDA (p = 0.06), although in opposite directions. Further, every doubling of PFOA or PFOS increased the risk of LRTI by 27% (HR: 1.27 (1.01, 1.59)) and 54% (HR: 1.54 (1.11, 2.15)), respectively. Similar tendencies were seen for URTI and the group of other infections. For GIs, the opposite pattern of association was seen as HR's were consistently below 1 (PFOA, HR: 0.55 (0.32, 0.95)). DISCUSSION: We found an association between PFOS and the overall risk of infectious disease, and between PFOS and PFOA exposures and the risk of LRTI's. These results are in agreement with previous findings from the OCC, in which maternal PFOS and PFOA concentrations were positively associated with the number of days that the children experienced fever, thereby suggesting that PFOS and PFOA may affect the prevalence of both mild and more severe infectious diseases even in a rather low-exposed population.

Severity of COVID-19 at elevated exposure to perfluorinated alkylates.

BACKGROUND: The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are immunotoxic and may contribute to an association with disease severity. METHODS: From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome. RESULTS: Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an unadjusted odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease. Among those hospitalized, the fully adjusted OR for getting into intensive care or expiring was 5.18 (1.29, 20.72) when based on plasma samples obtained at the time of diagnosis or up to one week before. CONCLUSIONS: Measures of individual exposures to immunotoxic PFASs included short-chain PFBA known to accumulate in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of a more severe course of COVID-19. Given the low background exposure levels in this study, the role of exposure to PFASs in COVID-19 needs to be ascertained in populations with elevated exposures.

Prenatal Exposures to Perfluoroalkyl Acids and Associations with Markers of Adiposity and Plasma Lipids in Infancy: An Odense Child Cohort Study.

BACKGROUND: Perfluoroalkyl acids (PFAA) are repellants that cross the placental barrier, enabling interference with fetal programming. Maternal PFAA concentrations have been associated with offspring obesity and dyslipidemia in childhood and adulthood, but this association has not been studied in infancy. OBJECTIVES: We investigated associations between maternal PFAA concentrations and repeated markers of adiposity and lipid metabolism in infancy. METHODS: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAA: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 649 women. Offspring were examined at birth (n=613) and at 3 months (n=602) and 18 months (n=503) of age. Total cholesterol, LDL, HDL, and triglyceride were evaluated at 3 months (n=262) and 18 months (n=198) of age. Mixed effects linear regression models estimated associations between PFAA and standardized (SDS) body mass index (BMI), ponderal index, and waist circumference. Associations between PFAA and body fat% (BF%) and plasma lipids SDS at 3 months and 18 months of age were investigated with linear regression models. RESULTS: PFNA and PFDA were associated with higher BMI SDS [adjusted ß=0.26; 95% confidence interval (CI): 0.03, 0.49 and ß=0.58; 95% CI: -0.03, 1.19, respectively, for 1-ng/mL increases] and ponderal index SDS (ß=0.36; 95% CI: 0.13, 0.59 and ß=1.02; 95% CI: 0.40, 1.64, respectively) at 3 and 18 months of age (pooled) in girls. Corresponding estimates for boys were closer to the null but not significantly different from estimates for girls. In boys and girls (combined), PFNA and PFDA were associated with BF% at age 3 months (for 1-ng/mL PFDA, ß=0.40; 95% CI: 0.04, 0.75), and PFDA was associated with total cholesterol SDS at 18 months (ß=1.06; 95% CI: 0.08, 2.03) (n=83). DISCUSSION: Prenatal PFAA were positively associated with longitudinal markers of adiposity and higher total cholesterol in infancy. These findings deserve attention in light of rising rates of childhood overweight conditions and dyslipidemia. https://doi.org/10.1289/EHP5184.

Serum Perfluoroalkyl Substances, Vaccine Responses, and Morbidity in a Cohort of Guinea-Bissau Children.

BACKGROUND: Perfluoroalkyl substances (PFAS) are a group of widely used persistent chemicals with suspected immunotoxic effects. OBJECTIVES: The present study aimed to examine the association between infant PFAS exposure and antibody responses to measles vaccination as well as morbidity in a low-income country. METHODS: In a randomized controlled trial, children from Guinea-Bissau, West Africa, were followed from inclusion (4-7 months of age) through 2 years of age. Half the children received two measles vaccinations (at inclusion and at 9 months of age), and the other half received only one (at 9 months of age). In a subset of 237 children, six PFAS were quantified in serum at inclusion, and measles antibody concentrations were assessed at inclusion and at approximately 9 months and 2 years of age. At inclusion and at the 9-month visit, mothers were interviewed about infant morbidity. RESULTS: All but one child had detectable serum concentrations of all six PFAS, although levels were lower than seen elsewhere. A doubling in perfluorooctane sulfonic acid (PFOS) and perfluorodecanoic acid (PFDA) were associated with 21% (95% CI: 2, 37%) and 25% (95% CI: 1, 43%), respectively, lower measles antibody concentrations at the 9-month visit among the children who had received a measles vaccine at inclusion. Elevated serum PFAS concentrations were also associated with reduced prevaccination measles antibody concentrations and increased morbidity. DISCUSSION: The present study documents that PFAS exposure has reached West Africa and that infants show PFAS-associated increases in morbidity and decreases in measles-specific antibody concentrations before and after vaccination. These findings support the evidence on PFAS immunotoxicity at comparatively low serum concentrations. https://doi.org/10.1289/EHP6517.

Maternal phthalate exposure associated with decreased testosterone/LH ratio in male offspring during mini-puberty. Odense Child Cohort.

BACKGROUND: Phthalates are plastic softeners with anti-androgenic properties. Prenatal exposure has led to lower testosterone (T) levels and smaller testicles in adult rats. To our knowledge, no studies have examined associations between prenatal phthalate exposure and sex hormone concentrations in infants. OBJECTIVE: To study associations between phthalate exposure in Danish pregnant women and T, luteinizing hormone (LH), follicle stimulating hormone (FSH), Δ4-androstenedione (adion), 17α-hydroxyprogesterone (17-OHP) dehydroepiandrosterone sulfate (DHEAS) concentrations in their infants (N = 479) during mini-puberty. METHODS: Concentrations of 12 phthalate metabolites from six phthalate diesters were measured in urine samples collected from 2010 to 2012 from 479 pregnant women participating in the Odense Child Cohort at gestational week 28 (range 20.4-30.4). Serum T, LH, FSH, adion, 17-OHP, DHEAS, weight and height were measured approximately three months after expected date of birth. Associations between prenatal phthalate exposure and gonadotropin and androgen metabolite concentrations were estimated in boys and girls separately in adjusted linear regression models. RESULTS: T concentration was lower in boys prenatally exposed to phthalates. Maternal urinary concentrations of summed mono-iso-butyl and mono-n-butyl phthalate (∑MBPi+n) and summed metabolites of di-iso-nonyl phthalate (∑DiNPm) were associated with lower T/LH ratio in male offspring and a dose-response association was found. FSH was 14% (95% CI: 1; 25) lower among male offspring from mothers exposed to ∑DiNPm in the highest compared to the lowest tertile. No association was found for girls. CONCLUSION: Even in these low exposed children, we found a significant decrease in T/LH ratio during mini-puberty in boys prenatally exposed to phthalates, which may suggest impairment of Leydig cells. The children will be followed as they approach adrenarche and pubarche in order to assess if long-term adverse effects persist.

Environmental chemical exposures among Greenlandic children in relation to diet and residence.

The objective of this study was to identify geographic, dietary, and other predictors for childhood exposure to perfluoroalkyl substances (PFASs), polychlorinated biphenyls (PCBs), and methylmercury in Greenlandic children. The study includes cross-sectional data from 367 Greenlandic children aged 7 to 12 years examined during 2012-2015. A parent or guardian participated in a structured interview, and a blood sample from the child was analysed for PFASs, PCBs and total mercury. Predictors for the environmental exposures were identified using linear regression. Area of residence was found to have the strongest explanatory power, accounting for 24% to 68% of the variance in the serum concentrations. Information about diet was available for two-thirds of the children, and among these, consumption of traditional Greenlandic food accounted for 2% to 10% of the variance in the biomarker concentrations. Models including all predictors associated with at least one of the environmental chemicals explained 19% to 54% of the total variance. In conclusion, area is a likely proxy for a traditional marine diet, and together area and diet constitute the most important predictors of exposure to methylmercury, PCBs and PFASs among Greenlandic children.

Perfluoroalkyl substances and glycemic status in pregnant Danish women: The Odense Child Cohort.

BACKGROUND: Perfluoroalkyl substances (PFASs) are persistent chemicals with suspected endocrine disrupting abilities applied in consumer products. PFASs have potentially modulating effects on glucose homeostasis. Insulin resistance prevails during third trimester of pregnancy, and this challenge of glucose homeostasis may reveal putative effects of PFAS concentrations on glycemic status. OBJECTIVE: To investigate associations between five serum PFASs and glucose-related outcomes in pregnant Danish women based on their risk of gestational diabetes mellitus (GDM). METHODS: In the prospective Odense Child Cohort serum concentrations of five PFASs - perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) - were measured at median gestational week (GW) 11 in pregnant women. An oral glucose tolerance test (OGTT) was performed at GW 28. The statistical analysis was conducted among 158 women with high GDM risk and 160 women with low GDM risk matched by gestational age. Multiple linear regression models were performed to estimate associations between PFAS concentrations and glucose, insulin, C-peptide, homeostatic model of assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-%ß), and insulin sensitivity (Matsuda index) during the 2-h OGTT. RESULTS: In women with high risk for GDM, a two-fold increase in PFHxS concentration was significantly associated with increased fasting glucose, fasting insulin and HOMA-IR after adjusting for age, parity, educational level and pre-pregnancy BMI. Adjusting for the same confounders, a doubling in PFNA concentration was associated with higher fasting insulin and HOMA-%ß. In women with low GDM risk, no associations were found between PFAS concentrations and glucose-related outcomes. CONCLUSION: PFHxS and PFNA concentrations were associated with impaired glycemic status in metabolically vulnerable pregnant women and might further enhance the risk of developing GDM.