To Örebro University

We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicals related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment. (C) 2007 Elsevier Inc. All rights reserved.

Plasticizers are a category of chemicals extensively used in consumer products and, consequently, their presence is ubiquitous in the indoor environment. In the present study, an analytical method has been developed for the quantification of plasticizers (7 legacy phthalate esters (LPEs) and 14 alternative plasticizers (APs)) in indoor floor dust based on ultrasonic and vortex extraction, Florisil fractionation and GC-(EI)-MS analysis. Dust samples (n = 54) were collected from homes, offices, and daycare centers from different EU countries (Belgium, the Netherlands, Ireland and Sweden). Method LOQs ranged from 0.2 to 5 mu g/g. Tri-n-hexyl trimellitate (THTM) was not detected in any sample, whereas dimethyl phthalate (DMP), diphenyl phthalate and acetyl triethyl citrate (ATEC) were detected only in 6, 2 and 1 out of 54 samples, respectively. The highest concentrations of plasticizers were measured in Swedish offices, at a mean concentration of total plasticizers of 1800 mu g/g, followed by Swedish daycare centers at 1200 and 670 mu g/g for winter and spring sampling, respectively. Generally, the contribution of APs was slightly higher than for LPEs for all indoor environments (mean contribution 60% and 40%, respectively based on contributions per indoor environment). For the APs, main contributors were DINP in Belgian homes (28%), Swedish offices (60%), Swedish daycare centers (48%), and Dutch offices (31%) and DEHT in Belgian (28%), Irish (40%) and Dutch homes (37%) of total APs. The predominant LPE was bis-2-ethylhexyl-phthalate (DEHP) with a mean contribution varying from 60% to 85% of total LPEs. Human exposure was evaluated for dust ingestion and dermal absorption using hazard quotients (HQs) of plasticizers (ratio between average daily doses and the reference dose). None of the HQs of plasticizers exceeded 1, meaning that the risk for adverse human health effects from these plasticizers via dust ingestion and dermal absorption is unlikely.

BACKGROUND: Associations between per- and polyfluoroalkyl substances (PFAS), mainly PFOS and PFOA, and increased blood lipids have been reported primarily from cross-sectional studies. The aim of the present study was to investigate associations between multiple PFAS and blood lipids in a longitudinal fashion.

METHODS: A total of 864 men and women aged 70 years and free from lipid medication were included from the PIVUS study, 614 and 404 of those were reinvestigated at age 75 and 80. At all three occasions, eight PFAS were measured in plasma using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were also measured in plasma at all three occasions. Mixed-effects linear regression models were used to examine the relationship between the changes in PFAS levels and changes in lipid levels.

RESULTS: Changes in plasma levels of six out of the eight investigated PFAS were positively associated with changes in plasma lipids after adjustment for sex, change in body mass index (BMI), smoking, physical activity, statin use (age was the same in all subjects), and correction for multiple testing. For example, changes in perfluorodecanoic acid (PFDA) were positively associated with the changes in total cholesterol (β: 0.23, 95% confidence interval (CI): 0.14 to 0.32), triglycerides (β: 0.08, 95% CI: 0.04-0.12) and HDL-cholesterol (β: 0.08, 95% CI: 0.04-0.11).

CONCLUSION: In this longitudinal study with three measurements over 10 years of both plasma PFAS and lipids, changes in six out of the eight investigated PFAS were positively associated with changes in plasma lipids, giving further support for a role of PFAS exposure in human lipid metabolism.

The level of PFAS (per- and polyfluorinated alkyl substances) contamination in freshwater and terrestrial Swedish environments in 2013/2014 was assessed by analyzing a range of perfluorinated alkyl acids, fluorotelomer acids, sulfonamides, sulfonamidoethanols and polyfluoralkyl phosphate diesters (diPAPs) in predator bird eggs. Stable isotopes ((13)C and (15)N) were analyzed to elucidate the dietary source. The tawny owl (Strix aluco, n=10) and common kestrel (Falco tinnunculus, n=40), two terrestrial species, and the osprey (Pandion haliaetus, n=30), a freshwater specie were included. In addition, a temporal trend (1997-2001, 2008-2009, 2013) in osprey was studied as well. The PFAS profile was dominated by perfluorooctane sulfonic acid (PFOS) in eggs from osprey and tawny owl, while for common kestrel perfluorinated carboxylic acids (∑PFCA) exceeded the level of PFOS. PFOS concentration in osprey eggs remained at the same level between 1997 and 2001 and 2013. For the long-chained PFCAs, there were a significant increase in concentrations in osprey eggs between 1997 and 2001 and 2008-2009. The levels of PFOS and PFCAs were about 10 and five times higher, respectively, in osprey compared to tawny owl and common kestrel. Evidence of direct exposure from PFCA precursor compounds to birds in both freshwater and terrestrial environment was observed. Low levels of diPAPs were detected in a few samples of osprey (<0.02-2.4ng/g) and common kestrel (<0.02-0.16ng/g) eggs, and 6:2 FTSA was detected in a majority of the osprey eggs (<6.3-52ng/g). One saturated telomer acid (7:3 FTCA), which is a transformation marker from precursor exposure, was detected in all species (<0.24-2.7ng/g). The (15)N data showed higher levels in osprey eggs compared to tawny owl and common kestrel, indicating that they feed on a 2-3 times higher trophic level. We conclude that ospreys are continuously exposed to PFAS at levels where adverse toxic effects have been observed in birds.

In 2015, the Rockefeller Foundation-Lancet Commission launched a report introducing a novel approach called Planetary Health and proposed a concept, a strategy and a course of action. To discuss the concept of Planetary Health in the context of Europe, a conference entitled: "Europe That Protects: Safeguarding Our Planet, Safeguarding Our Health" was held in Helsinki in December 2019. The conference participants concluded with a need for action to support Planetary Health during the 2020s. The Helsinki Declaration emphasizes the urgency to act as scientific evidence shows that human activities are causing climate change, biodiversity loss, land degradation, overuse of natural resources and pollution. They threaten the health and safety of human kind.

Global, regional, national, local and individual initiatives are called for and multidisciplinary and multisectorial actions and measures are needed. A framework for an action plan is suggested that can be modified for local needs. Accordingly, a shift from fragmented approaches to policy and practice towards systematic actions will promote human health and health of the planet. Systems thinking will feed into conserving nature and biodiversity, and into halting climate change.

The Planetary Health paradigm ‒ the health of human civilization and the state of natural systems on which it depends ‒ must become the driver for all policies.

BACKGROUND: Particulate matter (PM) is classified as a group 1 human carcinogen. Previous experimental studies suggest that particles in diesel exhaust induce oxidative stress, inflammation and DNA damage in kidney cells, but the evidence from population studies linking air pollution to kidney cancer is limited.

METHODS: We pooled six European cohorts (N = 302,493) to assess the association of residential exposure to fine particles (PM_2.5), nitrogen dioxide (NO₂), black carbon (BC), warm season ozone (O₃) and eight elemental components of PM_2.5 (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) with cancer of the kidney parenchyma. The main exposure model was developed for year 2010. We defined kidney parenchyma cancer according to the International Classification of Diseases 9th and 10th Revision codes 189.0 and C64. We applied Cox proportional hazards models adjusting for potential confounders at the individual and area-level.

RESULTS: The participants were followed from baseline (1985-2005) to 2011-2015. A total of 847 cases occurred during 5,497,514 person-years of follow-up (average 18.2 years). Median (5-95%) exposure levels of NO₂, PM_2.5, BC and O₃ were 24.1 μg/m³ (12.8-39.2), 15.3 μg/m³ (8.6-19.2), 1.6 10^-5 m^-1 (0.7-2.1), and 87.0 μg/m³ (70.3-97.4), respectively. The results of the fully adjusted linear analyses showed a hazard ratio (HR) of 1.03 (95% confidence interval [CI]: 0.92, 1.15) per 10 μg/m³ NO₂, 1.04 (95% CI: 0.88, 1.21) per 5 μg/m³ PM_2.5, 0.99 (95% CI: 0.89, 1.11) per 0.5 10^-5 m^-1 BCE, and 0.88 (95% CI: 0.76, 1.02) per 10 μg/m³ O₃. We did not find associations between any of the elemental components of PM_2.5 and cancer of the kidney parenchyma.

CONCLUSION: We did not observe an association between long-term ambient air pollution exposure and incidence of kidney parenchyma cancer.

Background and objective: Persistent organic pollutants (POPs) are stable organic compounds generated through different industrial activities. Liver is involved in the metabolism of POPs, and hence exposure to POPs may interfere with liver function. Although a few studies have shown adverse effects of POPs on liver function, large-scale studies involving humans are lacking. We performed this large population-based cross-sectional study to assess the associations between different POPs and liver dysfunction biomarkers.

Methods: A total of 992 individuals (all aged 70 years, 50% males) were recruited as part of Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. The total toxic equivalency (TEQ) value was calculated for seven mono-ortho and two non-ortho substituted polychlorinated biphenyls (PCBs) and octachloro-p-dibenzodioxin (OCDD) to assess their toxicological effects. The association of TEQ values, summary measures of 16 PCBs (sum of PCBs) and three organochlorine pesticides (sum of OC pesticides) with liver dysfunction biomarkers (bilirubin; alkaline phosphatase, ALP; alanine amino-transferase, ALT; and gamma-glutamyltransferase, GGT) was analyzed utilizing linear regression analysis.

Results: The mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (beta=0.71, P=0.008), while sum of OC pesticide concentrations was negatively associated with ALP (beta= -0.02, P=0.002) after adjusting for various potential confounders. When analyzed individually, a number of different POPs were associated with ALP, ALT and bilirubin. No such association with GGT was observed.

Conclusion: Various POPs including PCBs, OCDD and pesticides were associated with the liver dysfunction biomarkers bilirubin, ALT and ALP, suggesting adverse effects on liver function from these environmental pollutants. (C) 2014 Elsevier Inc. All rights reserved.

INTRODUCTION: Effects of environmental contaminants (ECs) on endocrine systems have been reported, but few studies assessed associations between ECs and sex hormones (SH) in elderly. Aim of this study was to investigate whether blood concentrations of four classes of ECs were associated with SH concentrations in elderly.

METHODS: Samples from participants of the cross-sectional population-based Prospective Investigation of the Vasculature in Uppsala Seniors study (PIVUS, 70-year-old men and women, n=1016) were analysed using validated mass spectrometry-based methods for SH (testosterone (T), dihydrotestosterone (DHT), estrone and estradiol (E2)); 23 persistent organic pollutants (POPs); 8 perfluoroalkyl substances (PFAS); 4 phthalates and 11 metals. SH binding globulin (SHBG) was analysed using immunoassay. The measured concentrations were normalized, and the values converted to a z-scale. Linear regression analyses were conducted to assess association between concentration of the SH, SHBG and E2/T (aromatase enzyme index, AEI) with the ECs. Multiple linear regression analyses were performed to model the relationships.

RESULTS: The strongest associations were observed with the polychlorinated biphenyls (PCBs). In men, the strongest associations with concentrations of SH and SHBG were seen for PCBs containing >5 chlorine, monoethyl phthalate (MEP), Ni and Cd; and in women, with PCBs, MEP, several of the PFAS, Cd, Co, and Ni. Difference in the effect of ECs on AEI between men and women were observed. Area under the ROC curve for the models predicting abnormal values of SH and SHBG (> 0.75) due to the effects of ECs was observed for T, DHT, and E2 in men, and for E2 and SHBG in women.

CONCLUSIONS: Results of this study suggest that in elderly subjects, concentrations of many ECs associated with concentrations of SH and SHBG, and AEI. Further studies are needed to confirm the findings and to assess effect of the pollutants on endocrine system function in elderly.

BACKGROUND AND OBJECTIVES: The pesticide metabolite p,p'-DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p'-DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p'-DDE with LV mass.

METHODS: p,p'-DDE was measured in plasma from 70-year-old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70-, 75- and 80- years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques.

RESULTS: We found that p,p'-DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p'-DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%).

CONCLUSION: The obesogenic effect of p,p'-DDE is a major determinant responsible for the association of p,p'-DDE with LV mass.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous. Previous studies have found associations between PFAS and thyroid hormones in maternal and cord sera, but the results are inconsistent. To further address this research question, we used mixture modeling to assess the associations with individual PFAS, interactions among PFAS chemicals, and the overall mixture.

METHODS: We collected data through the Health Outcomes and Measures of the Environment (HOME) Study, a prospective cohort study that between 2003 and 2006 enrolled 468 pregnant women and their children in the greater Cincinnati, Ohio region. We assessed the associations of maternal serum PFAS concentrations measured during pregnancy with maternal (n = 185) and cord (n = 256) sera thyroid stimulating hormone (TSH), total thyroxine (TT₄), total triiodothyronine (TT₃), free thyroxine (FT₄), and free triiodothyronine (FT₃) using two mixture modeling approaches (Bayesian kernel machine regression (BKMR) and quantile g-computation) and multivariable linear regression. Additional models considered thyroid autoantibodies, other non-PFAS chemicals, and iodine deficiency as potential confounders or effect measure modifiers.

RESULTS: PFAS, considered individually or as mixtures, were generally not associated with any thyroid hormones. A doubling of perfluorooctanesulfonic acid (PFOS) had a positive association with cord serum TSH in BKMR models but the 95% Credible Interval included the null (β = 0.09; 95% CrI: -0.08, 0.27). Using BKMR and multivariable models, we found that among children born to mothers with higher thyroid peroxidase antibody (TPOAb), perfluorooctanoic acid (PFOA), PFOS, and perfluorohexanesulfonic acid (PFHxS) were associated with decreased cord FT₄ suggesting modification by maternal TPOAb status.

CONCLUSIONS: These findings suggest that maternal serum PFAS concentrations measured in the second trimester of pregnancy are not strongly associated with thyroid hormones in maternal and cord sera. Further analyses using robust mixture models in other cohorts are required to corroborate these findings.

BACKGROUND: Parabens, suspected as endocrine-disrupting chemicals, are nearly ubiquitous in the human body and exposure to these chemicals during pregnancy may disrupt thyroid hormones homeostasis and even affect fetal growth, although the impacts are still unclear.

OBJECTIVES: We aimed to estimate associations of maternal urinary paraben concentrations with cord serum thyroid hormones and birth weight.

METHODS: A subset of 437 mother-newborn pairs were included from a prospective birth cohort with five parabens quantified in maternal urine and seven thyroid function indicators measured in cord serum samples. Multivariable linear regression models and elastic net regression (ENR) models were applied to explore associations between individual and mixtures of prenatal urinary paraben concentrations and thyroid hormones and birth weight, respectively.

RESULTS: Maternal urinary ethyl-paraben (EtP) concentrations were associated with increased cord serum total triiodothyronine levels (TT3) [percent change: 1.51%; 95% confidence interval (CI): 0.20%, 2.74%; p=0.017]. Urinary propyl-paraben (PrP) levels predicted higher thyroid peroxidase antibodies (percent change: 4.19%, 95% CI: 0.20%, 8.44%; p=0.041). Maternal urinary EtP and butyl-paraben (BuP) concentrations were significantly positively associated with birth weight [regression coefficient, (β)=40.9g, 95% CI: 3.99, 76.6; p=0.030; β=62.1g, 95% CI: 8.70, 115; p=0.023, for EtP and BuP, respectively]. In sex-stratified analyses, positive relationship between EtP levels and birth weight was observed in boys. Urinary EtP concentrations predicted higher TT3 levels in cord serum samples, assessing parabens as a chemical mixture with ENR models.

CONCLUSIONS: Prenatal exposure to parabens may affect thyroid hormone indicators with increased serum TT3 levels and associate with higher birth weight, especially in boys. The underlying biological mechanisms and effects of prenatal paraben exposures on disruption of thyroid function homeostasis and potential impacts of childhood growth and development needed to be further investigated.

Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures > 80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003-0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005-0.05 range. Very few associations with p < 0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs.

BACKGROUND: It has been suggested that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors with a potential to influence fat mass.

OBJECTIVE: The primary hypothesis tested was that we would find positive relationships for PFAS vs measures of adiposity.

METHODS: In 321 subjects all aged 50 years in the POEM study, five PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA)) were measured in serum together with a Dual-energy X-ray absorptiometry (DXA) scan for determination of fat and lean mass. Whole-body magnetic resonance imaging scan was performed and the body was divided into >1 million voxels. Voxel-wise statistical analysis was carried out by a novel method denoted Imiomics.

RESULTS: PFOS and PFHxS, did not show any consistent associations with body composition. However, PFOA, and especially PFNA and PFDA, levels were inversely related to most traditional measures reflecting the amount of fat in women, but not in men. In the Imiomics analysis of tissue volume, PFDA and PFNA levels were inversely related to the volume of subcutaneous fat, mainly in the arm, trunk and hip regions in women, while no such clear relationship was seen in men. Also, the visceral fat content of the liver, the pericardium, and the gluteus muscle were inversely related to PFDA and PFNA in women.

DISCUSSION: Contrary to our hypothesis, some PFAS showed inverse relationships vs measurements of adiposity.

CONCLUSION: PFOS and PFHxS levels in plasma did not show any consistent associations with body composition, but PFOA, and especially PFNA and PFDA were inversely related to multiple measures reflecting the amount of fat, but in women only.

Background: Polychlorinated biphenyls (PCBs) and dioxin given to experimental animals increase the blood pressure. We therefore investigated if circulating levels of persistent organic pollutants (POPs) were related to hypertension in a population-based sample of men and women.

Methods: One thousand and sixteen subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Twenty-three POPs were analyzed using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Hypertension was defined as a systolic blood pressure >= 140 mmHg or a diastolic blood pressure >= 90 mmHg, and/or use of antihypertensive medication.

Results: Seven hundred and thirty-two subjects (72%) showed hypertension. When the POPs were treated as continuous variables and adjusted for gender only, two PCBs with a low number of chlorine atoms (PCB 105 and 118) were related to prevalent hypertension. Also the OC pesticide p,p'-DDE was related to hypertension. The strongest of these associations was seen for p,p'-DDE (OR 135 for a 1 SD change, 95% CI 1.17-1.56, p < 0.0001). Following further adjustment also for BMI, smoking status, education level and exercise habits, only p,p'-DDE was still significantly related to hypertension (OR 1.23 for a 1 SD change, 95% CI 1.06-1.43, p=0.006).

Conclusion: In this cross-sectional analysis of an elderly population, high levels of circulating levels of p,p'-DDE were associated with prevalent hypertension, further strengthening the experimental findings that POPs might influence blood pressure. (C) 2013 Elsevier Inc. All rights reserved.

Background and objective: During recent years, some persistent organic pollutants (POPs) have been linked to atherosclerosis. One group of POPs, the poly- and perfluoroalkyl substances (PFASs) have not been investigated with regard to atherosclerotic plaques.

Methods: Carotid artery atherosclerosis was assessed by ultrasound in 1016 subjects aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants' plasma by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS).

Results: No significant linear associations were observed between the PFASs and intima-media thickness (IMT), or the echogenicity in the intima-media complex (IM-GSM, a marker of lipid infiltration in the artery) when men and women were analyzed together. Neither was occurrence of carotid plaques related to PFASs levels. However, highly significant interactions were observed between some PFASs and sex regarding both IM-GSM and plaque prevalence. Perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), were all related to IM-GSM in a positive fashion in women (p=0.002-0.003), while these relationships were negative in men. The levels of PFUnDA were significantly related to carotid plaque in women (OR 1.59, 95%CI 1.03-2.43, p=0.03), but not in men (OR 0.93, 95%CI 0.62-1.42, p=0.75).

Conclusions: In this cross-sectional study, a pronounced gender difference was observed regarding associations between some PFASs, especially the long-chain PFUnDA, and markers of atherosclerosis, with more pronounced relationships found in women. These findings suggest a sex-specific role for PFASs in atherosclerosis.

Background: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects. To date, very little effort has been devoted to the study of the metabolism of PCBs on a genome-wide level.

Objectives: Here, we conducted a genome-wide association study (GWAS) to identify genomic regions involved in the metabolism of PCBs.

Methods: Plasma levels of 16 PCBs ascertained in a cohort of elderly individuals from Sweden (n=1016) were measured using gas chromatography-high resolution mass spectrophotometry (GC-HRMS). DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project. Association testing was performed in a linear regression framework under an additive model.

Results: Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2. The SNP with the strongest association was rs8109848 (p=3.7 x 10(-13)), mapping to an intronic region of CYP2B6. Moreover, when all PCBs were conditioned on PCB-99, further signals were revealed for PCBs -74, -105 and -118, mapping to the same genomic region. The lead SNPs were rs8109848 (p=3.8 x 10(-12)) for PCB-118, rs4802104 (p= 1.4 x 10(-9)) for PCB-74 and rs4803413 (p=2.5 x 10(-9)) for PCB-105, all of which map to CYP2B6.

Conclusions: In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus. These findings show that CYP2B6 is of importance for the metabolism of PCBs in humans, and may help to identify individuals who may be susceptible to PCB toxicity. (C) 2015 The Authors. Published by Elsevier Inc.

When reporting circulating levels of persistent organic pollutants (POPs), usually lipid-normalized values are given. However, animal experiments and some human data indicate that exposure to POPs may change lipid values. The aim of the present study is to investigate if POP levels can predict future changes in levels of circulating lipids. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, lipids were measured at age 70 and at age 75 in 598 subjects without lipid-lowering medication. Twenty-three different POPs, including 16 polychlorinated biphenyls (PCBs), five organochlorine pesticides, one dioxin (OCDD) and one flame retardant brominated compound (BDE47) were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) at age 70. Strong relationships were seen among the baseline levels of the non-dioxin-like PCBs 194, 206 and 209 and the degree of increase in total serum cholesterol and LDL-cholesterol during the 5 year follow-up. These relationships were generally stronger when lipidnormalized levels were used compared to wet-weight based levels. On the contrary, for two of the pesticides, hexachlorobenzene and trans-nonachlordane, levels were inversely related to the change in LDL-cholesterol, with strongest associations found using wet-weight based levels. PCBs 194, 206 and 209 were inversely related to the change in HDL-cholesterol, in particular for wet-weight based levels. However, these relationships were only significant for wet-weight PCB 194 following adjustment for multiple testing. None of the POPs was related to the change in serum triglycerides. When investigating the association between the change in total serum cholesterol and LDL-cholesterol across different categories of change in BMI, we noted robust results especially in the group with stable BMI, suggesting that the observed relationships were not due to fluctuations in BMI over time. In conclusion, POPs are related to the change in lipids over time, especially LDL-cholesterol. This may explain why POP exposure previously has been linked to atherosclerosis and cardiovascular disease.

BACKGROUND: Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear.

OBJECTIVES: We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI).

MATERIALS AND METHODS: We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993-2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics.

RESULTS: Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (ΣDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (ΣDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (ΣDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and ΣDBP, while current smokers had higher ΣDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, ΣDiBP, and ΣDEHP.

CONCLUSION: Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non-Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations.

Celiac disease (CD) is a systemic immune-mediated disorder with increased frequency in the developed countries over the last decades implicating the potential causal role of various environmental triggers in addition to gluten. Herein, we apply determination of perfluorinated alkyl substances (PFAS) and combine the results with the determination of bile acids (BAs) and molecular lipids, with the aim to elucidate the impact of prenatal exposure on risk of progression to CD in a prospective series of children prior the first exposure to gluten (at birth and at 3 months of age). Here we analyzed PFAS, BAs and lipidomic profiles in 66 plasma samples at birth and at 3 months of age in the Type 1 Diabetes Prediction and Prevention (DIPP) study (n = 17 progressors to CD, n = 16 healthy controls, HCs). Plasma PFAS levels showed a significant inverse association with the age of CD diagnosis in infants who later progressed to the disease. Associations between BAs and triacylglycerols (TGs) showed different patterns already at birth in CD progressors, indicative of different absorption of lipids in these infants. In conclusion, PFAS exposure may modulate lipid and BA metabolism, and the impact is different in the infants who develop CD later in life, in comparison to HCs. The results indicate more efficient uptake of PFAS in such infants. Higher PFAS exposure during prenatal and early life may accelerate the progression to CD in the genetically predisposed children.

Background and objective: Major risk factors for congestive heart failure (CHF) are myocardial infarction, hypertension, diabetes, atrial fibrillation, smoking, left ventricular hypertrophy (LVH) and obesity. However, since these risk factors only explain part of the risk of CHF, we investigated whether persistent organic pollutants (POPs) might also play a role.

Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, left ventricular ejection fraction, (EF), E/A-ratio and isovolumic relaxation time (IVRT), were determined by echocardiography and serum samples of 21 POPs were analyzed in serum measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 998 subjects all aged 70 years.

Results: In this cross-sectional analysis, high levels of several of the polychlorinated biphenyls (PCB congeners 99, 118, 105, 138, 153, and 180) and octachlorodibenzo-p-dioxin (OCDD) were significantly related to a decreased EF. Some POPs were also related to a decreased E/A-ratio (PCBs 206 and 209). All the results were adjusted for gender, hypertension, diabetes, smoking, LVH and BMI, and subjects with myocardial infarction or atrial fibrillation were excluded from the analysis.

Conclusions: Circulating levels of POPs were related to impairments in both left ventricular systolic and diastolic function independently of major congestive heart failure risk factors, suggesting a possible role of POPs in heart failure. (C) 2013 Elsevier Inc. All rights reserved.

Background: In our daily life, we are exposed to perfluoroalkyl substances (PFAS) with possible health implications. The main exposure route for these substances is diet but comparative studies on how dietary habits influence exposure are lacking.

Objectives: To examine the relations between blood levels of PFAS and adherence to three predefined dietary patterns (a WHO recommended diet, a Mediterranean-like diet, and a Low-Carbohydrate High-Protein (LCHP) diet) in an elderly Swedish population.

Methods: Dietary data from 7-day food records and serum concentrations of PFAS were obtained from a 70-year-old Swedish population (n=844), the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The Healthy Diet Indicator score (based on WHO recommendations), the Mediterranean Diet Score and LCHP score were used to assess adherence. Multivariate linear regression was used to assess the associations between eight major PFAS and adherence to each dietary pattern.

Results: The WHO recommended diet was positively associated with perfluorohexane sulfonic acid (PFHxS). The LCHP diet was positively related to four out of eight PFAS; namely, perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUnDA). The Mediterranean-like diet was positively associated with most PFAS; namely perfluorooctanoic acid (PFOA), perfluorooctane sulfonamide (PFOSA), PFHxS, PFNA, PFDA, and PFUnDA.

Conclusions: All dietary patterns were positively associated with blood levels of PFAS. The highest body burden of PFAS was found in individuals with high adherence to a Mediterranean-like diet, whilst individuals who more closely followed the officially recommended diet displayed a lower body burden of these compounds.

BACKGROUND: Prospective cohort studies evaluating the temporal trends of background-level persistent organic pollutants (POPs) and their potential negative health effects in humans are needed.

OBJECTIVE: The objectives of this study are to examine the five year longitudinal trend in chlorinated and brominated (Cl/Br) POP concentrations in a sample of elderly individuals and to investigate the relationship between gender, changes in body weight, plasma lipid levels and POP concentrations.

METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, plasma samples were collected from the same individuals over a 5 year period. Originally 992 subjects (all aged 70) were sampled between 2001 and 2004 and 814 returning subjects (all aged 75) were sampled again from 2006 to 2009. Plasma concentrations of 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and one polybrominated diphenylether (BDE 47) were determined using high-throughput 96-well plate solid phase extraction and gas chromatography-high resolution mass spectrometry (GC-HRMS).

RESULTS: During the 5-year follow-up, plasma concentrations of all POPs significantly decreased (p < 0.00001). Median reductions ranged from 4% (PCB105) to 45% (PCB 99), with most reductions being in the 30-40% range. For most POPs, a larger decline was seen in men than in women. The relationship between the weight change and change in POP concentrations was generally negative, but a positive relationship between lipid levels and POP concentrations when expressed as wet-weight was observed. In general, similar changes in POP concentrations and their relationships to body weight were observed regardless of using either wet-weight (pg/mL) or lipid-normalized (ng/g lipid) concentrations.

CONCLUSION: In this longitudinal cohort study, gender and minor, but varying changes in body weight and lipid levels greatly influenced the individual-based changes in POP concentrations. In general, our findings suggest that men and women with larger decreases in body weight and greater increases in lipid levels have the slowest decline in body burden of POPs. Based on the results from this study, either wet-weight or lipid normalized concentrations can be used to determine the percent change in POP concentrations and their relationships to physiological changes and differences.

BACKGROUND: In 2012, drinking water contaminated with per- and polyfluoroalkyl substances (PFASs), foremost perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) at levels over 20ng/L and 40ng/L, respectively, was confirmed in Uppsala, Sweden.

OBJECTIVES: We assessed how a longitudinally sampled cohort's temporal trend in PFAS plasma concentration was influenced by their residential location and determined the plausible association or disparity between the PFASs detected in the drinking water and the trend in the study cohort.

METHODS: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort provided plasma samples three times from 2001 to 2014. Individuals maintaining the same zip code throughout the study (n = 399) were divided into a reference (no known PFAS exposure), low, intermediate and high exposure area depending on the proportion of contaminated drinking water received. Eight PFASs detected in the majority (75%) of the cohort's plasma samples were evaluated for significant changes in temporal PFAS concentrations using a random effects (mixed) model.

RESULTS: PFHxS plasma concentrations continued to significantly increase in individuals living in areas receiving the largest percentage of contaminated drinking water (p < 0.0001), while PFOS showed an overall decrease. The temporal trend of other PFAS plasma concentrations did not show an association to the quality of drinking water received.

CONCLUSIONS: The distribution of contaminated drinking water had a direct effect on the trend in PFHxS plasma levels among the different exposure groups, resulting in increased concentrations over time, especially in the intermediate and high exposure areas. PFOS and the remaining PFASs did not show the same relationship, suggesting other sources of exposure influenced these PFAS plasma trends.

Although people are exposed daily to per- and polyfluorinated alkyl substances (PFASs), the biological consequences are poorly explored. The health risks associated with PFAS exposure are currently based on chemical analysis with a weak correlation to potential harmful effects in man and animals. In this study, we show that perfluorooctane sulfonic acid (PFOS), often the most enriched PFAS in the environment, can be transferred via bacteria to higher organisms such as Caenorhabditis elegans. C. elegans nematodes were exposed to PFOS directly in buffer or by feeding on bacteria pretreated with PFOS, and this led to distinct gene expression profiles. Specifically, heavy metal and heat shock associated genes were significantly, although inversely, expressed following the different PFOS exposures. The innate immunity receptor for microbial pathogens, clec-60, was shown for the first time to be down-regulated by PFOS. This is in line with a previous study indicating that PFOS is associated with children's susceptibility to certain infectious diseases. Furthermore, bar-1, a gene associated with various cancers was highly up-regulated only when C. elegans were exposed to PFOS pretreated live bacteria. Furthermore, dead bacterial biomass had higher binding capacity for linear and isomeric PFOS than live bacteria, which correlated to the higher levels of PFOS detected in C. elegans when fed the treated E. toll, respectively. These results reveal new aspects concerning trophic chain transport of PFOS.

BACKGROUND: Some endocrine disrupting chemicals (EDC), are "obesogens" and have been associated with overweight and obesity in children. Daily exposure to different classes of EDCs demands for research with mixtures approach.

OBJECTIVES: This study evaluates the association, considering sex-specific effects, between prenatal exposure to EDC mixture and children's body fat at seven years of age. METHODS: A total of 26 EDCs were assessed in prenatal urine and serum samples from first trimester in pregnancy from 737 mother-child pairs participating in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. An indicator for children's "overall body fat" was calculated, using principal component analysis (PCA), based on BMI, percent body fat, waist, and skinfolds measured at seven years of age. Weighted quantile sum (WQS) regression was used to assess associations between EDC mixture and children's body fat.

RESULTS: Principal component (PC1) represented 83.6 % of the variance, suitable as indicator for children's "overall body fat", with positive loadings of 0.40-0.42 for each body fat measure. A significant interaction term, WQS*sex, confirmed associations in the opposite direction for boys and girls. Higher prenatal exposure to EDC mixture was borderline significant with more "overall body fat" for boys (Mean β = 0.20; 95 % CI: -0.13, 0.53) and less for girls (Mean β = -0.23; 95 % CI: -0.58, 0.13). Also, higher exposure to EDC mixture was borderline significant with more percent body fat (standardized score) for boys (Mean β = 0.09; 95 % CI: -0.04, 0.21) and less for girls (Mean β = -0.10 (-0.26, 0.05). The chemicals of concern included bisphenols, phthalates, PFAS, PAH, and pesticides with different patterns for boys and girls.

DISCUSSION: Borderline significant associations were found between prenatal exposure to a mixture of EDCs and children's body fat. The associations in opposite directions suggests that prenatal exposure to EDCs may present sex-specific effects on children's body fat.

BACKGROUND: Carbamate pesticides exposure have been linked with adverse health effects during developmental period. Based on 377 mother-child pairs from Sheyang Mini Birth Cohort Study, the present study aimed to assess carbofuranphenol exposure of three-year-old children and explore the associations between prenatal or postnatal carbofuranphenol exposures and neurodevelopmental indicators.

METHODS: Urinary carbofuranphenol concentrations were measured by gas chromatography-tandem mass spectrometry. Neural developmental quotient (DQ) of children was evaluated using Gesell Developmental Schedules. Generalized linear models were used to examine the associations between carbofuranphenol concentrations and neurodevelopment.

RESULTS: Geometric mean, geometric standard deviation, median, inter quartile range of postnatal urinary carbofuranphenol concentrations were 0.653 μg/L, 9.345 μg/L, 0.413 μg/L, 0.150-1.675 μg/L, respectively. Postnatal carbofuranphenol level showed negatively significant trend in language DQ [beta (β) = -0.121; 95% confidence interval (95% CI): 0.212, -0.031; p value (p) = 0.008] and total average DQ (β = -0.059, 95% CI: 0.115, -0.003; p = 0.035). Prenatal carbofuranphenol level showed negative correlations with children's adaptive DQ (β = -0.755; 95% CI: 1.257, -0.254; p = 0.003), social DQ (β = -0.341; 95% CI: 0.656, -0.027; p = 0.032) and total average DQ (β = -0.349; 95% CI: 0.693, -0.005; p = 0.047).

CONCLUSION: The results of the present study supposed children in agricultural region of China are widely exposed to carbamate pesticides, and both prenatal and postnatal exposure to carbamate pesticides may lead to neurodevelopmental effect.

BACKGROUND: Triclosan is a broad-spectrum antimicrobial, and was thought to affect intrauterine development, but the mechanism remains unclear.

OBJECTIVE: To explore the association between prenatal triclosan exposure and birth outcomes.

METHODS: Based on 726 mother-child pairs from the Sheyang Mini Birth Cohort Study (SMBCS), we used the available (published) data of triclosan in maternal urines, the hormones including thyroid-related hormones, gonadal hormones in cord blood, and adipokines, trimethylamine-N-oxide (TMAO) and its precursors in cord blood to explore possible health effects of triclosan on birth outcomes through assessing different hormones and parameters, using Bayesian mediation analysis.

RESULTS: Maternal triclosan exposure was associated with ponderal index (β = 0.317) and head circumference (β = -0.172) in generalized linear models. In Bayesian mediation analysis of PI model, estradiol (β = 0.806) and trimethylamine (TMA, β = 0.164) showed positive mediation effects, while total thyroxine (TT4, β = -0.302), leptin (β = -2.023) and TMAO (β = -0.110) showed negative mediation effects. As for model of head circumference, positive mediation effects were observed in free thyroxine (FT4, β = 0.493), TMA (β = 0.178), and TMAO (β = 0.683), negative mediation effects were observed in TT4 (β = -0.231), testosterone (β = -0.331), estradiol (β = -1.153), leptin (β = -2.361), choline (β = -0.169), betaine (β = -0.104), acetyl-L-carnitine (β = -0.773).

CONCLUSION: The results indicated triclosan can affect intrauterine growth by interfering thyroid-related hormones, gonadal hormones, adipokines, TMAO and its precursors.