Maternal serum levels of perfluoroalkyl substances in early pregnancy and offspring birth weight.

BACKGROUND: Perfluoroalkyl substances (PFASs) are widespread, bioaccumulating, and persistent and show placental transfer. Emerging research indicates associations between prenatal exposure and low birth weight. The aim of this study was to assess the associations between first trimester exposure to PFASs and birth weight (BW) in the Swedish Environmental, Longitudinal, Mother and child, Asthma and allergy (SELMA) study and examine whether associations differ between girls and boys. METHODS: Eight PFASs were analyzed in maternal serum (median: 10 weeks of pregnancy). Associations between prenatal PFAS exposure and birth outcomes with BW, BW for gestational age, and birth small for gestational age (SGA) were assessed in 1533 infants, adjusted for potential confounders and stratified by sex. RESULTS: Increased maternal perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were associated with lower BW, lower BW for gestational age, and SGA birth. Associations were significant only in girls, where prenatal exposure in the upper quartile was associated with a 93-142-g lower BW when compared with that of the lowest quartile exposure. The associations were not mediated by effects on gestational age. CONCLUSIONS: We found associations between prenatal exposure for five different PFASs and birth weight, with more pronounced associations in girls than in boys.

Internal exposure to perfluoroalkyl substances (PFASs) and biological markers in 101 healthy 1-year-old children: associations between levels of perfluorooctanoic acid (PFOA) and vaccine response.

Perfluoroalkyl substances (PFASs) are a complex group of man-made chemicals with high stability and mobility leading to ubiquitous environmental contamination and accumulation in the food chain. In human serum/plasma samples, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are the lead compounds. They are immunotoxic in experimental animals, and epidemiological studies provided evidence of a diminished production of vaccine antibodies in young children. However, information on children of the first year of age is missing but relevant, as they have a relatively high exposure if breastfed, and may have a higher susceptibility as their immune system is developing. In a cross-sectional study with 101 healthy 1-year-old children, internal levels of persistent organic pollutants and a broad panel of biological parameters were investigated at the end of the 1990s. Additional analysis of PFASs resulted in plasma levels (mean ± SD) of PFOA and PFOS of 3.8 ± 1.1 and 6.8 ± 3.4 µg/L, respectively, in the 21 formula-fed children, and of 16.8 ± 6.6 and 15.2 ± 6.9 µg/L in the 80 children exclusively breastfed for at least 4 months. The study revealed significant associations between levels of PFOA, but not of PFOS, and adjusted levels of vaccine antibodies against Haemophilus influenza type b (Hib, r = 0.32), tetanus (r = 0.25) and diphtheria (r = 0.23), with no observed adverse effect concentrations (NOAECs) determined by fitting a 'knee' function of 12.2, 16.9 and 16.2 µg/L, respectively. The effect size (means for PFOA quintiles Q1 vs. Q5) was quantified to be - 86, - 54 and - 53%, respectively. Furthermore, levels of PFOA were inversely associated with the interferon gamma (IFNÉ£) production of ex-vivo lymphocytes after stimulation with tetanus and diphtheria toxoid, with an effect size of - 64 and - 59% (means Q1 vs. Q5), respectively. The study revealed no influence of PFOA and PFOS on infections during the first year of life and on levels of cholesterol. Our results confirmed the negative associations of PFAS levels and parameters of immune response observed in other epidemiological studies, with high consistency as well as comparable NOAECs and effects sizes for the three vaccine antibodies investigated, but for PFOA only. Due to reduction of background levels of PFASs during the last 20 years, children in Germany nowadays breastfed for a long duration are for the most part not expected to reach PFOA levels at the end of the breastfeeding period above the NOAECs determined.

Fluorine detection in the lung tissue of a worker with interstitial pulmonary fibrosis and long-term occupational exposure to polytetrafluoroethylene and perfluorooctanoic acid.

Exposure to polytetrafluoroethylene (PTFE), a compound used in nonstick cookware coating and a variety of other applications, is known to cause acute lung injury and granulomatous pneumonitis. It is uncertain whether PTFE and compounds used in its manufacture, such as perfluorooctanoic acid (PFOA), cause chronic lung disease. Here we report a case of interstitial pulmonary fibrosis in a 71-year-old man who died following a brief illness clinically suspected to be acute respiratory distress syndrome. He had a 25-year history of occupational exposure to PTFE and PFOA. At postmortem examination, the lungs demonstrated diffuse alveolar damage (DAD) superimposed on interstitial pulmonary fibrosis. The interstitial fibrosis lacked fibroblast foci and exhibited basilar and subpleural accentuation with focal microscopic honeycombing. Within the fibrotic lung parenchyma were scattered giant cells containing birefringent translucent particles. Scanning electron microscopy and energy-dispersive x-ray spectroscopy (SEM-EDS) were performed. A majority of the birefringent particles demonstrated a prominent peak for fluorine by EDS analysis. This is the first report to document the presence of fluorine, an elemental constituent of PTFE and PFOA, in fibrotic lung tissue. Careful evaluation of other individuals with long-term exposure to PTFE and/or PFOA appears warranted to better elucidate the spectrum of pulmonary disease associated with these compounds.

Making the invisible visible: results of a community-led health survey following PFAS contamination of drinking water in Merrimack, New Hampshire.

BACKGROUND: In March 2016, citizens of Merrimack, New Hampshire, learned that their public water supply was contaminated with perfluorooctanoic acid (PFOA). A subsequent state-led investigation revealed widespread contamination of both public and private well water with PFOA and several related chemicals, broadly termed per- and polyfluoroalkyl substances (PFAS). This research examines the local response to PFAS contamination of the public water system and well water in Merrimack and the results from the health survey administered by a local advocacy group, Merrimack Citizens for Clean Water (MCFCW). METHODS: MCFCW designed and implemented a community health survey (n = 596) representing 213 households exposed to PFAS through drinking water. The surveys were conducted in the summer of 2017. Respondents used an online survey platform to report demographic information, exposure sources, and health conditions. Logistic regression was used to analyze the community-based health survey results . RESULTS: There were several important associations that warrant further investigation and more immediate attention, especially: 1) elevated incidence of developmental, autoimmune and kidney disorders among those under 18 years of age; 2) elevated levels of health concerns, multiple health concerns, autoimmune disorders, and reproductive disorders among women, 3) elevated levels of health concerns, multiple health conditions, cardiovascular, respiratory, reproductive, and liver disorders in those with industrial occupational exposures, and; 4) elevated incidence of health concerns, cardiovascular, and developmental disorders among those who have been living in Merrimack for a long time versus newer residents. CONCLUSIONS: The limitations inherent in the study design warrant caution in interpreting the results, however the associations found in this study merit further investigation. This health survey highlights foremost the critical gap in information-lack of access to blood testing, medical monitoring and physician guidance of PFAS-exposed residents. This study provides a model for conducting community-based health studies to advocate for pathways to state supported biomonitoring and medical monitoring for those exposed to industrial toxins and to take into consideration the human health burden in shaping the future of chemical regulation.

Serum Perfluorooctanoic Acid and Birthweight: An Updated Meta-analysis With Bias Analysis.

BACKGROUND: A recent meta-analysis of 15 studies found a change in birthweight of -12.8 g (95% CI = -23.1, -2.38) per ng/ml PFOA in maternal or cord blood and -27.1 g (-50.6, -3.6) per log ng/ml PFOA. Almost all studies were done in low-exposed populations. There are nine new studies, adding 6,019 births to the previous 6,937 births. METHODS: We conducted a meta-analysis of 24 studies. To combine all results, we approximated results for untransformed PFOA from nine studies using log-transformed PFOA. We also included another large study, excluded from previous analyses, in a sensitivity analysis. RESULTS: We found a change of birthweight of -10.5 g (-16.7, -4.4) for every ng/ml PFOA in maternal or cord blood. After adding one previously excluded large study, we found little evidence of an association (-1.0 g; 95% CI = -2.4, 0.4). Restricting to studies where blood was sampled from mothers early in the pregnancy or shortly before conception (5,393 births), we found little association of PFOA with birthweight (-3.3 g [-9.6, 3.0]). In studies where blood was sampled late in the pregnancy (7563 pregnancies), lower birthweight was associated with higher PFOA (-17.8 [-25.0, -10.6]). CONCLUSION: Present human evidence provides only modest support for decreased birthweight with increasing PFOA. Studies with a wide range of exposure, and studies with blood sampled early in pregnancy, showed little or no association of PFOA with birthweight. These are studies in which confounding and reverse causality would be of less concern.

Prenatal exposure to perfluoroalkyl substances and adipocytokines: the HOME Study.

OBJECTIVE: Gestational perfluoroalkyl substances exposure has been associated with decreased birthweight. We determined if gestational perfluoroalkyl substances exposure was associated with fetal metabolic markers using data from the HOME Study, a prospective birth cohort of pregnant women and their children in Cincinnati, Ohio. METHODS: Maternal serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid, and perfluorohexane sulfonic acid were quantified. We measured neonatal adipocytokine (leptin and adiponectin) concentrations in umbilical cord serum, and estimated percent differences with a 2-fold increase in maternal perfluoroalkyl substances concentrations among 230 mother-infant pairs. RESULTS: Median maternal serum PFOA and PFOS concentrations were 5.6 ng/mL and 14 ng/mL, respectively. Leptin was positively correlated with infant birthweight (p < 0.001). There were no statistically significant associations between maternal perfluoroalkyl substances and neonatal adipocytokine concentrations; each 2-fold increase in PFOA was associated with a non-significant increase in leptin (5%; 95% CI: -10, 22) and adiponectin (7%; 95% CI: -4, 19). CONCLUSION: Despite known associations with reduced birthweight, gestational serum perfluoroalkyl substances concentrations were not associated with neonatal adipocytokine concentrations. Further exploration of pathways of perfluoroalkyl substances associated changes in birthweight may help identify biomarkers that could be used to identify at-risk populations and develop interventions.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

BACKGROUND: Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. METHODS: In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. FINDINGS: Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. INTERPRETATION: A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. FUNDING: Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

A novel method to generate monocyte-derived dendritic cells during coculture with HaCaT facilitates detection of weak contact allergens in cosmetics.

The in vitro sensitization assay LCSA (Loose-fit Coculture-based Sensitization Assay) has proved reliable for the detection of contact sensitizers in the past. However, the coculture of human monocyte-derived dendritic cells (DCs) with primary human keratinocytes (KCs) in serum-free medium is relatively complex compared to other sensitization assays which use continuous cell lines. To facilitate high-throughput screening of chemicals, we replaced KCs with the HaCaT cell line under various culture conditions. Coculture of HaCaT with peripheral blood mononuclear cells in serum-supplemented medium leads to generation of CD1a+/CD1c+ DCs after addition of GM-CSF, IL-4, and TGF-ß1 (as opposed to CD1a-/CD1c- DCs which arise in the "classic" LCSA coculture). These cells resemble monocyte-derived DCs generated in monoculture, but, unlike those, they show a marked upregulation CD86 after treatment with contact allergens. All of the nine sensitizers in this study were correctly identified by CD1a+/CD1c+ DCs in coculture with HaCaT. Among the substances were weak contact allergens such as propylparaben (which is false negative in the local lymph node assay in mice) and resorcinol (which was not detected by CD1a-/CD1c- DCs in the "classic" LCSA). The level of CD86 upregulation on CD1a+/CD1c+ DCs was higher for most allergens compared to CD1a-/CD1c- DCs, thus improving the assay's discriminatory power. Three out of four non-sensitizers were also correctly assessed by the coculture assay. A false-positive reaction to caprylic (octanoic) acid confirms earlier results that some fatty acids are able to induce CD86 on DC in vitro. In conclusion, change of the LCSA protocol led to reduction of time and cost while even increasing the assay's sensitivity and discriminatory power.

An epidemic of allergic contact dermatitis caused by a new allergen, caprylhydroxamic acid, in moisturizers.

BACKGROUND: In 2016, dermatologists in Finland suspected contact allergy in several patients using moisturizers under the trade name Apobase®. Following a formulation change, Phenostat™, which is a mixture of phenoxyethanol, caprylhydroxamic acid, and methylpropanediol, was used as a preservative in Apobase® moisturizers in Finland. OBJECTIVES: To confirm the suspected contact allergy to Apobase® cream, oily cream, and/or lotion, and to identify the specific contact allergen and define its optimal patch test concentration. METHODS: Thirty-nine patients with suspected contact allergy to Apobase® creams or lotion were patch tested in four Finnish dermatological clinics. The patch tests included old and new Apobase® formulas and their preservative agents: phenoxyethanol, methylpropanediol, and dilution series of Phenostat™ and caprylhydroxamic acid or its potassium salt. RESULTS: The patch tests showed positive reactions to the new Apobase® formulas, Phenostat™, and caprylhydroxamic acid or its potassium salt, but not to the old Apobase® formulas, methylpropanediol, or phenoxyethanol. CONCLUSIONS: We found a new contact allergen, caprylhydroxyamic acid, which caused an epidemic of allergic contact dermatitis in patients using moisturizers containing this preservative. Whether the sensitizing capacity of caprylhydroxamic acid depends on the other chemicals used in Apobase® moisturizers needs further investigation.

Risk Belief and Attitude Formation From Translated Scientific Messages About PFOA, an Environmental Risk Associated With Breast Cancer.

Evidence regarding possible environmental causes of breast cancer is advancing. Often, however, the public is not informed about these advances in a manner that is easily understandable. This research translates findings from biologists into messages at two literacy levels about perfluorooctanoic acid (PFOA), a possible environmental contributor to breast cancer. The Heuristic Systematic Model (HSM) was used to investigate how ability, motivation, and systematic and heuristic processing lead to risk beliefs and, ultimately, to negative attitudes for individuals receiving translated scientific messages about PFOA. Participants (N = 1,389) came from the Dr. Susan Love Research Foundation's Army of Women. Findings indicated that ability, in the form of translated messages, predicted systematic processing, operationalized as knowledge gain, which was negatively associated with formation of risk beliefs that led to negative attitudes toward PFOA. Heuristic processing cues, operationalized as perceived message quality and source credibility, were positively associated with risk beliefs, which predicted negative attitudes about PFOA. Overall, more knowledge and lower literacy messages led to lower perceived risk, while greater involvement and ratings of heuristic cues led to greater risk perceptions. This is an example of a research, translation, and dissemination team effort in which biologists created knowledge, communication scholars translated and tested messages, and advocates were participants and those who disseminated messages.

The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection.

Perfluorooctanoic acid (PFOA) is an environmental contaminant that could induce developmental cardiotoxicity in a chicken embryo, which may be alleviated by l-carnitine. To explore the roles of reactive oxygen species (ROS) and nitric oxide (NO) in such changes and the potential effects of l-carnitine, fertile chicken eggs were exposed to PFOA via an air cell injection, with or without l-carnitine co-treatment. The ROS and NO levels in chicken embryo hearts were determined with electron spin resonance (ESR), and the protein levels of the nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) p65 and inducible nitric oxide synthase (iNOS) in chicken embryo hearts were assessed with western blotting. The results of ESR indicated that PFOA exposure induced an elevation in the ROS levels in ED19 chicken embryo hearts and hatchling chicken hearts, while l-carnitine could alleviate such changes. Meanwhile, increased NO levels were observed in ED19 embryo hearts and hatchling hearts following PFOA exposure, while l-carnitine co-treatment exerted modulatory effects. Western blotting revealed that p65 translocation in ED19 embryo hearts and hatchling hearts was enhanced by PFOA, while l-carnitine co-treatment alleviated such changes. iNOS expression levels in ED19 embryo hearts followed the same pattern as NO levels, while a suppression of expression was observed in hatchling hearts exposed to PFOA. ROS/NF-κB p65 and iNOS/NO seem to be involved in the late stage (ED19 and post hatch) of PFOA-induced developmental cardiotoxicity in a chicken embryo. l-carnitine could exert anti-oxidant and NO modulatory effects in the developing chicken embryo hearts, which likely contribute to its cardioprotective effects.

A Simple Pharmacokinetic Model of Prenatal and Postnatal Exposure to Perfluoroalkyl Substances (PFASs).

Most children are exposed to perfluoroalkyl substances (PFASs) through placental transfer, breastfeeding, and other environmental sources. To date, there are no validated tools to estimate exposure and body burden during infancy and childhood. In this study, we aimed to (i) develop a two-generation pharmacokinetic model of prenatal and postnatal exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and perfluorohexanesulfonate (PFHxS); and to (ii) evaluate it against measured children's levels in two studies. We developed a pharmacokinetic model consisting of a maternal and a child compartment to simulate lifetime exposure in women and transfer to the child across the placenta and through breastfeeding. To evaluate the model, we performed simulations for each mother-child dyad from two studies in which maternal PFAS levels at delivery and children's PFAS levels were available. Model predictions based on maternal PFAS levels, sex of child, body weight, and duration of breastfeeding explained between 52% and 60% of the variability in measured children's levels at 6 months of age and between 52% and 62% at 36 months. Monte Carlo simulations showed that the daily intake through breastfeeding and resulting internal PFAS levels can be much higher in nursing infants than in mothers. This pharmacokinetic model shows potential for postnatal exposure assessment in the context of epidemiological studies and risk assessment.

Influence of the uncertainty in the validation of PBPK models: A case-study for PFOS and PFOA.

Physiologically-based pharmacokinetic (PBPK) models are mathematical representations of the human body aimed at describing the time course distribution of chemicals in human tissues. Since parameterization of PBPK models is based on empirical estimation and experimental data, simulation results may have high degree of uncertainty. As a consequence, the reliability of model validation is highly affected. In this study, the parametric uncertainty associated with PBPK models developed for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were analyzed and the different validation approaches were discussed for a case-study in Tarragona County (NE of Spain). Physicochemical parameters and dietary intake of PFOS and PFOA were estimated from previous investigations performed in Tarragona County. A sensitivity analysis (SA) was performed to understand the degree of influence of input parameters on the final outcomes. The uncertainty of the PBPK models' outcome was assessed by propagating the parametric uncertainty using the Latin Hypercube Sampling (LHS) technique. The elimination constants (Tm and Kt) as well as the Free fraction and the Intake, were the most influential parameters according to the SA results, being up to 83% for PFOS and 99.9% for PFOA. The validation of the PBPK model, which was performed using different approaches, showed clear discrepancies in the visual validation when compared with the statistical analysis.

Estimating effect of environmental contaminants on women's subfecundity for the MoBa study data with an outcome-dependent sampling scheme.

Motivated by the need from our on-going environmental study in the Norwegian Mother and Child Cohort (MoBa) study, we consider an outcome-dependent sampling (ODS) scheme for failure-time data with censoring. Like the case-cohort design, the ODS design enriches the observed sample by selectively including certain failure subjects. We present an estimated maximum semiparametric empirical likelihood estimation (EMSELE) under the proportional hazards model framework. The asymptotic properties of the proposed estimator were derived. Simulation studies were conducted to evaluate the small-sample performance of our proposed method. Our analyses show that the proposed estimator and design is more efficient than the current default approach and other competing approaches. Applying the proposed approach with the data set from the MoBa study, we found a significant effect of an environmental contaminant on fecundability.

A cohort incidence study of workers exposed to perfluorooctanoic acid (PFOA).

OBJECTIVES: Determine if perfluorooctanoic acid (PFOA) is associated with an incident disease in an occupational cohort. METHODS: We interviewed 3713 workers or their next of kin in 2008-2011, and sought medical records for self-reported disease. These workers were a subset of a previously studied cohort of 32,254 community residents and workers. We estimated historical PFOA serum levels via a job-exposure matrix based on over 2000 serum measurements. Non-occupational exposure from drinking water was also estimated. Lifetime serum cumulative dose (combining occupational and non-occupational exposure) was our exposure metric. We studied 17 disease outcomes with more than 20 validated cases. RESULTS: The median measured serum level was 113 ng/mL in 2005 (n=1881), compared with 4 ng/mL in the US. Ulcerative colitis (10-year lag) showed a significant trend (p≤0.05) with increasing dose (quartile rate ratios (RRs)=1.00, 3.00, 3.26, 6.57, n=28, p for trend=0.05), similar to earlier findings in the community study. Rheumatoid arthritis (no lag) showed a positive trend in a categorical trend test (RRs=1.00, 2.11, 4.08, 4.45, n=23, p for trend=0.04). Positive non-significant trends were also observed for prostate cancer, non-hepatitis liver disease and male hypothyroidism, which have been implicated in other studies. A significant negative trend was found for bladder cancer and asthma with medication. No marked trends were seen for high cholesterol, which had been seen in the community study. CONCLUSIONS: Ulcerative colitis and rheumatoid arthritis were positively linked to PFOA exposure among workers. Data were limited by small numbers, under-representation of hard-to-trace decedents and few low-exposed referents.

PFOA and PFOS serum levels and miscarriage risk.

BACKGROUND: Serum concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were assessed in relation to miscarriage in a population of mid-Ohio River Valley residents highly exposed to PFOA through contaminated drinking water. METHODS: Serum PFOA and PFOS concentrations were measured in 1129 women in 2005-2006 who reported pregnancy outcomes in follow-up interviews between 2008 and 2011. In the analysis, we included 1438 reported live births, stillbirths, and miscarriages with estimated conception dates after the serum measurements. Preconception serum levels of PFOA and PFOS were analyzed in relation to miscarriage using logistic regression and generalized estimating equations. RESULTS: There was little evidence of association between PFOA and miscarriage. For PFOS, when including all reported prospective pregnancies, the odds ratio of miscarriage per log ng/ml increase was 1.21 (95% confidence interval = 0.94-1.55); in subanalyses restricted to each woman's first pregnancy conceived after the serum measurement, the odds ratio was 1.34 (1.02-1.76). Categorical analyses showed elevated odds ratios for the top 4 quintiles relative to the first quintile, without a monotonic trend. Positive associations between PFOS and miscarriage were strongest among nulligravid pregnancies. CONCLUSIONS: In this prospective study of miscarriage in a population exposed to high levels of PFOA and background levels of PFOS, we found little evidence of association with serum levels of PFOA and limited evidence of association with serum levels of PFOS.

Menstrual cycle characteristics in fertile women from Greenland, Poland and Ukraine exposed to perfluorinated chemicals: a cross-sectional study.

STUDY QUESTION: Does perfluorooctane sulfonate (PFOS) and perfluorooctanate (PFOA) exposure disrupt the menstrual cyclicity? SUMMARY ANSWER: The female reproductive system may be sensitive to PFOA exposure, with longer menstrual cycle length at higher exposure. WHAT IS KNOWN ALREADY: PFOS and PFOA are persistent man-made chemicals. Experimental animal studies suggest they are reproductive toxicants but epidemiological findings are inconsistent. STUDY DESIGN, SIZE, DURATION: A cross-sectional study including 1623 pregnant women from the INUENDO cohort enrolled during antenatal care visits between June 2002 and May 2004 in Greenland, Poland and Ukraine. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information on menstrual cycle characteristics was obtained by questionnaires together with a blood sample from each pregnant woman. Serum concentrations of PFOS and PFOA were measured by liquid chromatography tandem mass spectrometry. Multiple imputations were performed to account for missing data. The association between PFOS/PFOA and menstrual cycle length (short cycle: ≤24 days, long cycle: ≥32 days) and irregularities (≥7 days in difference between cycles) was analyzed using logistic regression with tertiles of exposure. Estimates are given as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS AND THE ROLE OF CHANCE: Higher exposure levels of PFOA were associated with longer menstrual cycles in pooled estimates of all three countries. Compared with women in the lowest exposure tertile, the adjusted OR of long cycles was 1.8 (95% CI: 1.0; 3.3) among women in the highest tertile of PFOA exposure. No significant associations were observed between PFOS exposure and menstrual cycle characteristics. However, we observed a tendency toward more irregular cycles with higher exposure to PFOS [OR 1.7 (95% CI: 0.8; 3.5)]. The overall response rate was 45.3% with considerable variation between countries (91.3% in Greenland, 69.1% in Poland and 26.3% in Ukraine). LIMITATIONS, REASONS FOR CAUTION: Possible limitations in our study include varying participation rates across countries; a selected study group overrepresenting the most fertile part of the population; retrospective information on menstrual cycle characteristics; the determination of cut-points for all three outcome variables; and lacking information on some determinants of menstrual cycle characteristics, such as stress, physical activity, chronic diseases and gynecological disorders, thus confounding cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: The generalizability of the study results is restricted to fertile women who manage to conceive and women who do not use oral contraceptives when getting pregnant or within 2 months before getting pregnant. To our knowledge only one previous epidemiological study has addressed the possible association between perfluorinated chemical exposure and menstrual disturbances. Though pointing toward different disturbances in cyclicity, both studies suggest that exposure to PFOA may affect the female reproductive function. This study contributes to the limited knowledge on effects of exposure to PFOA and PFOS on female reproductive function and suggests that the female reproductive system may be affected by environmental exposure to PFOA. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from Aarhus University Research Foundation. The collection of questionnaire data and blood samples was part of the INUENDO project supported by The European Commission (Contract no. QLK4-CT-2001-00 202), www.inuendo.dk. The Ukrainian part of the study was possible by a grant from INTAS (project 012 2205). Determination of PFOA and PFOS in serum was part of the CLEAR study (www.inuendo.dk/clear) supported by the European Commission's 7th Framework Program (FP7-ENV-2008-1-226217). No conflict of interest declared.

Inverse association of colorectal cancer prevalence to serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in a large Appalachian population.

BACKGROUND: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the development and progression of colorectal cancer (CRC). However, the link between these compounds and CRC remains unknown. In this cross-sectional study, we investigated the association of CRC diagnosis to PFOA and PFOS blood levels in a large Appalachian population. METHODS: Participants were 47,359 adults ≥ 21 years of age and residing in six PFOA-contaminated water districts in the mid-Ohio Valley (N = 47,151 cancer-free adults, 208 cases of primary CRC). All participants completed a comprehensive health survey between 2005 and 2006; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history was assessed via self report and cancer diagnosis confirmed via chart review. RESULTS: CRC showed a strong inverse, dose-response association with PFOS serum levels (odds ratio (OR) adjusted for potential confounders = 0.2, 95% confidence interval (CI) 0.2,0.3) for highest vs. lowest quartile of PFOS, P-trend < 0.00001) and a significant, but more modest inverse association with PFOA (adjusted OR = 0.6 (CI 0.4, 0.9) for highest vs. lowest quartile, P-trend = 0.001). These inverse associations were stronger in those diagnosed within the previous 6 years and resident in the same water district for a minimum of 10-15 years preceding assessment. The relationship between PFOA and CRC was also more pronounced in men and leaner adults, and showed a stronger linear trend at lower exposure levels. CONCLUSIONS: In this large cross-sectional study, we found a strong, inverse association between PFOS and likelihood of CRC diagnosis and a significant, although more modest inverse association between PFOA and CRC. If confirmed in prospective investigations, these findings may aid in identifying new strategies for CRC prevention and treatment and inform future studies regarding mechanisms underlying CRC pathogenesis.

Perfluorooctanoate exposure in a highly exposed community and parent and teacher reports of behaviour in 6-12-year-old children.

BACKGROUND: In toxicology studies, perfluorinated compounds affect fetal growth, development, viability, and postnatal growth. There are limited epidemiologic studies on child development. METHODS: We recruited and evaluated 321 children who participated in the C8 Health Project, a 2005-06 survey in a mid-Ohio Valley community highly exposed to perfluorooctanoate (PFOA) through contaminated drinking water. We examined associations between measured childhood PFOA serum concentration and mother and teacher reports of executive function (Behaviour Rating Inventory of Executive Function), attention deficit hyperactivity disorder (ADHD)-like behaviour (Conner's ADHD Diagnostic and Statistical Manual of Mental Disorders IV Scales), and behavioural problems (Behaviour Assessment System for Children) assessed 3 to 4 years later at ages 6-12 years. RESULTS: Overall, neither reports from mothers nor teachers provided clear associations between exposure and child behaviour. Mother reports, however, did suggest favourable associations between exposure and behaviour among boys and adverse associations among girls. On the composite scale from the Behaviour Rating Inventory of Executive Function (n = 318), PFOA exposure had a favourable association among boys (highest vs. lowest quartile ß = -6.39; 95% confidence interval [CI] -11.43, -1.35) and an adverse association among girls (highest vs. lowest quartile ß = 4.42; 95% CI -0.03, 8.87; interaction P = 0.01). Teacher reports (n = 189) replicated some, but not all of the sex interactions observed in mothers' reports. CONCLUSIONS: Aggregate results did not suggest adverse effects of PFOA on behaviour, but sex-specific results raise the possibility of differing patterns by sex. Results are not consistent between mothers' and teachers' reports. Effect modification by sex may warrant further investigation.

Mortality and cancer incidence in ammonium perfluorooctanoate production workers.

OBJECTIVE: To evaluate mortality and cancer incidence in a cohort of ammonium perfluorooctanoate (APFO) exposed workers. METHODS: We linked a combined cohort (n=9027) of employees from APFO and non-APFO production facilities in Minnesota to the National Death Index and to cancer registries of Minnesota and Wisconsin. Industrial hygiene data and expert evaluation were used to create a task-based job exposure matrix to estimate APFO exposure. Standardised mortality ratios were estimated using Minnesota population rates. HRs and 95% CIs for time-dependent cumulative APFO exposure were estimated with an extended Cox model. A priori outcomes of interest included cancers of the liver, pancreas, testes, kidney, prostate and breast, and mortality from cardiovascular, cerebrovascular and chronic renal diseases. RESULTS: Mortality rates in the APFO-exposed cohort were at or below the expected, compared with Minnesota. The HR for dying from the cancer and non-cancer outcomes of interest did not show an association with APFO exposure. Similarly, there was little evidence that the incident cancers were associated with APFO exposure. Compared to the non-exposed population, modestly elevated, but quite imprecise HRs were observed in the higher-exposure quartiles for bladder cancer (HR=1.66, 95% CI 0.86 to 3.18) and pancreatic cancer (HR=1.36, 95% CI 0.59 to 3.11). No association was observed between APFO exposure and kidney, prostate or breast cancers. CONCLUSIONS: This analysis did not support an association between occupational APFO exposure and the evaluated health endpoints, however, the study had limited power to evaluate some conditions of interest.