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Abstract An outbreak of SARS-CoV-2 (1 March to 10 May 2021) with an attack rate of 26.5% among approximately 1150 workers at a storage and distribution centre in England prompted a multidisciplinary outbreak investigation (5 May to 6 August 2021), with the aim of better understanding worker- and workplace-related risk factors for viral transmission in the warehousing sector. Overall, environmental factors (e.g., ventilation, humidity and temperature) were assessed to be appropriate at the facility. Nevertheless, 39 (51.3%) surface samples from across the site tested positive for low/ very low levels of SARS-CoV-2 RNA (Ct value ≥ 32.0 for all). Among the study participants, of whom 35.6% were confirmed or suspected cases, 95.5% reported having received COVID-19 prevention training, 100.0% reported handwashing, and 80.0% reported use of face coverings at work. Notably, 43.9% and 19.0% reported working with a symptomatic and a positive contact respectively. Furthermore, 80.5% and 46.3% had concerns regarding reduction in their income and future unemployment, respectively, due to self-isolation. The findings of this study suggest that, in addition to targeted workplace infection control measures and tailored work area specific risk assessments, an enhanced and equitable sick leave policy may help limit presenteeism and viral transmission in large workplaces.

Abstract EFSA requested its Scientific Committee to prepare a guidance document on appraising and integrating evidence from epidemiological studies for use in EFSA's scientific assessments. The guidance document provides an introduction to epidemiological studies and illustrates the typical biases, which may be present in different epidemiological study designs. It then describes key epidemiological concepts relevant for evidence appraisal. This includes brief explanations for measures of association, exposure assessment, statistical inference, systematic error and effect modification. The guidance then describes the concept of external validity and the principles of appraising epidemiological studies. The customisation of the study appraisal process is explained including tailoring of tools for assessing the risk of bias (RoB). Several examples of appraising experimental and observational studies using a RoB tool are annexed to the document to illustrate the application of the approach. The latter part of this guidance focuses on different steps of evidence integration, first within and then across different streams of evidence. With respect to risk characterisation, the guidance considers how evidence from human epidemiological studies can be used in dose–response modelling with several different options being presented. Finally, the guidance addresses the application of uncertainty factors in risk characterisation when using evidence from human epidemiological studies.

Abstract The European Commission asked EFSA to update its 2009 risk assessment on arsenic in food carrying out a hazard assessment of inorganic arsenic (iAs) and using the revised exposure assessment issued by EFSA in 2021. Epidemiological studies show that the chronic intake of iAs via diet and/or drinking water is associated with increased risk of several adverse outcomes including cancers of the skin, bladder and lung. The CONTAM Panel used the benchmark dose lower confidence limit based on a benchmark response (BMR) of 5% (relative increase of the background incidence after adjustment for confounders, BMDL05) of 0.06 μg iAs/kg bw per day obtained from a study on skin cancer as a Reference Point (RP). Inorganic As is a genotoxic carcinogen with additional epigenetic effects and the CONTAM Panel applied a margin of exposure (MOE) approach for the risk characterisation. In adults, the MOEs are low (range between 2 and 0.4 for mean consumers and between 0.9 and 0.2 at the 95th percentile exposure, respectively) and as such raise a health concern despite the uncertainties.

Abstract Background A SARS-CoV-2 outbreak with an attack rate of 14.3% was reported at a plastics manufacturing plant in England. Methods Between 23rd March and 13th May 2021, the COVID-OUT team undertook a comprehensive outbreak investigation, including environmental assessment, surface sampling, molecular and serological testing, and detailed questionnaires, to identify potential SARS-CoV-2 transmission routes, and workplace- and worker-related risk factors. Results While ventilation, indicated using real-time CO2 proxy measures, was generally adequate on-site, the technical office with the highest localized attack rate (21.4%) frequently reached peaks in CO2 of 2100ppm. SARS-CoV-2 RNA was found in low levels (Ct ≥35) in surface samples collected across the site. High noise levels (79dB) were recorded in the main production area, and study participants reported having close work contacts (73.1%) and sharing tools (75.5%). Only 20.0% of participants reported using a surgical mask and/or FFP2/FFP3 respirator at least half the time and 71.0% expressed concerns regarding potential pay decreases and/or unemployment due to self-isolation or workplace closure. Conclusions The findings reinforce the importance of enhanced infection control measures in manufacturing sectors, including improved ventilation with possible consideration of CO2 monitoring, utilising air cleaning interventions in enclosed environments, and provision of good-quality face masks (i.e., surgical masks or FFP2/FFP3 respirators) especially when social distancing cannot be maintained. Further research on the impacts of job security-related concerns is warranted.

There are important differences in the risk of SARS-CoV-2 infection and death depending on occupation. Infections in healthcare workers have received the most attention, and there are clearly increased risks for intensive care unit workers who are caring for COVID-19 patients. However, a number of other occupations may also be at an increased risk, particularly those which involve social care or contact with the public. A large number of data sets are available with the potential to assess occupational risks of COVID-19 incidence, severity, or mortality. We are reviewing these data sets as part of the Partnership for Research in Occupational, Transport, Environmental COVID Transmission (PROTECT) initiative, which is part of the National COVID-19 Core Studies. In this report, we review the data sets available (including the key variables on occupation and potential confounders) for examining occupational differences in SARS-CoV-2 infection and COVID-19 incidence, severity and mortality. We also discuss the possible types of analyses of these data sets and the definitions of (occupational) exposure and outcomes. We conclude that none of these data sets are ideal, and all have various strengths and weaknesses. For example, mortality data suffer from problems of coding of COVID-19 deaths, and the deaths (in England and Wales) that have been referred to the coroner are unavailable. On the other hand, testing data is heavily biased in some periods (particularly the first wave) because some occupations (e.g. healthcare workers) were tested more often than the general population. Random population surveys are, in principle, ideal for estimating population prevalence and incidence, but are also affected by non-response. Thus, any analysis of the risks in a particular occupation or sector (e.g. transport), will require a careful analysis and triangulation of findings across the various available data sets.

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent substances with surfactant and repellent properties. Municipal drinking water contaminated with PFAS had been distributed for decades to one third of households in Ronneby, Sweden. The source was firefighting foam used in a nearby airfield since the mid-1980s. Clean water was provided from December 16, 2013. Aims: The purpose was to estimate serum half-lives and their determinants in the study population for different PFAS. Methods: Up to ten blood samples were collected between 2014 and 2018 from 114 participants (age 4–84 years at entry, 53% female). 19 PFAS were analysed. Linear mixed models were used to estimate the half-lives. Results: Eight PFAS were increased in Ronneby: perfluorooctanoic acid (PFOA), perfluoropentane sulfonate (PFPeS), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), linear perfluorooctane sulfonate (L-PFOS) and three branched perfluorooctane sulfonates (1 m-PFOS, 3/4/5m-PFOS and 2/6m-PFOS). The mean estimated half-lives (in years) were 0.94 (95 %CI 0.86–1.02) for PFPeS, 2.47 (2.27–2.7) for PFOA, 2.67 (2.51–2.85) for 2/6m-PFOS, 2.73 (2.55–2.92) for L-PFOS, 3.43 (3.19–3.71) for 3/4/5m-PFOS, 4.52 (4.14–4.99) for PFHxS, 4.55 (4.14–5.06) for PFHpS, and 5.01 (4.56–5.55) for 1 m-PFOS.The most important determinants of a shorter half-life were young age, and better kidney function measured by estimated glomerular filtration rate and ratio of paired urine and serum PFAS levels, followed by female sex during their fertile period aged 15–50. Markers of gut inflammation and reduced permeability i.e. zonulin and calprotectin were also possibly associated with shorter half-life. The results also suggested a time-dependent PFAS elimination process, with more rapid elimination in the first year after the end of exposure. Conclusion: The half-life estimates are in line with past estimates for some PFAS such as PFOA, and the novel results for different PFOS isomers. These results provide observational support for elimination routes – renal, fecal and maternal.

Abstract Background Residents in a large area of North-Eastern Italy were exposed to perfluoroalkyl substances (PFAS) via drinking water. Studies on the association between PFAS and blood pressure levels are limited, and results are inconsistent. Using cross-sectional data from the Regional health surveillance program, we aimed to quantify the associations between PFAS serum concentrations and blood pressure and hypertension prevalence. Methods The study comprised 16,224 individuals aged 20–39 years. Pregnant women (n = 327), or individuals with missing information on the selected covariates (n = 111) were excluded, leaving 15,786 subjects for the analyses. Hypertension was defined as any self-reported diagnosis, use of antihypertensive drugs, or elevated systolic blood pressure (SBP ≥ 140 mmHg)/diastolic blood pressure (DBP ≥ 90 mmHg). Generalized additive models were used to investigate the relation between perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)) natural log (ln) transformed and by decile, and SBP, DBP, hypertension, adjusted for potential confounders. Results Both SBP and DBP increased significantly with an increase in the ln-transformed serum PFAS concentrations in a monotonic way. The predicted increase in SBP and DBP were 1.54 mmHg (95%CI 0.61–2.47), 1.60 mmHg (95%CI 0.92–2.27) from lowest to highest decile of PFOA. The associations were stronger for SBP in men and for DBP in women. One unit increase in each In-transformed PFAS was positively associated with an increased odd of hypertension in men: PFOA OR = 1.06 (1.01–1.11), PFOS OR = 1.13 (1.03–1.23), PFHxS OR = 1.08 (1.02–1.15), PFNA OR = 1.20 (1.02–1.40). Conclusions Our findings suggest that serum PFAS concentrations were associated with increased systolic and diastolic blood pressure in a large highly exposed young adult population. Although the magnitude of the observed effect was relatively small, if confirmed it would be of public health relevance since even small increases in blood pressure levels at the population level may be associated to a raised risk of adverse outcomes such as cardiovascular disease and target organ damage.

Abstract Background Exposures to perfluoroalkyl substances (PFAS) have shown positive associations with serum lipids in previous studies. While many studies on lipids investigated associations with perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), there are only a few studies regarding other PFAS, such as perfluorohexane sulfonic acid (PFHxS). The purpose of the current study is to investigate if associations with serum lipids were present, not only for serum PFOS and PFOA, but also for PFHxS, and if the associations with PFAS remained also in a comparison based only on residency in areas with contrasting exposure to PFAS. Methods 1945 adults aged 20–60 were included from Ronneby, Sweden, a municipality where one out of two waterworks had been heavily contaminated from aqueous fire-fighting foams, and from a nearby control area. The exposure was categorized based on either been living in areas with contrasting PFAS exposure or based on the actual serum PFAS measurements. Regression analyses of serum lipids were fitted against serum PFAS levels, percentile groups, smooth splines and between exposed and reference areas, adjusting for age, sex and BMI. Results Drinking water contamination caused high serum levels of PFOS (median 157 ng/ml) and PFHxS (median 136 ng/ml) and PFOA (median 8.6 ng/ml). These serum PFAS levels in the exposed groups were 5 to 100-fold higher than in the controls. In this population with mixed PFAS exposure, predominantly PFOS and PFHxS, PFAS exposure were positively associated with serum lipids. This was observed both when quantifying exposure as contrast between exposed and controls, and in terms of serum PFAS. Due to high correlations between each PFAS, we cannot separate them. Conclusions In conclusion, the present study provides further evidence of a causal association between PFAS and serum lipids, especially for PFHxS.

Background: Although perfluoroalkyl substances (PFASs) may be immunotoxic, evidence for this in humans is scarce. We studied the association between 4 PFASs (perfluorohexane sulfonate [PFHxS], perfluorooctanoic acid [PFOA], perfluorooctane sulfonate [PFOS] and perfluorononanoic acid [PFNA]) and circulating levels of several types of immune cells. Methods: Serum PFASs and white blood cell types were measured in 42,782 (2005–2006) and 526 (2010) adults from an area with PFOA drinking water contamination in the Mid-Ohio Valley (USA). Additionally, the major lymphocyte subsets were measured in 2010. Ln(cell counts) and percentages of cell counts were regressed on serum PFAS concentrations (ln or percentiles). Adjusted results were expressed as the percentage difference (95% CI) per interquartile range (IQR) increment of each PFAS concentration. Results: Generally positive monotonic associations between total lymphocytes and PFHxS, PFOA, and PFOS were found in both surveys (difference range: 1.12–7.33% for count and 0.36–1.77 for percentage, per PFAS IQR increment), and were stronger for PFHxS. These associations were reflected in lymphocyte subset counts but not percentages, with PFHxS positively and monotonically associated with T, B, and natural killer (NK) cell counts (range: 5.51–8.62%), PFOA and PFOS with some T-cell phenotypes, and PFOS with NK cells (range: 3.12–12.21%), the associations being monotonic in some cases. Neutrophils, particularly percentage (range: −1.74 to −0.36), showed decreasing trends associated with PFASs. Findings were less consistent for monocytes and eosinophils. Conclusion: These results suggest an association between PFHxS and, less consistently, for PFOA and PFOS, and total lymphocytes (although the magnitudes of the differences were small). The increase in absolute lymphocyte count appeared to be evenly distributed across lymphocyte subsets since associations with their percentages were not significant.

There are important differences in the risk of SARS-CoV-2 infection and death depending on occupation. Infections in healthcare workers have received the most attention, and there are clearly increased risks for intensive care unit workers who are caring for COVID-19 patients. However, a number of other occupations may also be at an increased risk, particularly those which involve social care or contact with the public. A large number of data sets are available with the potential to assess occupational risks of COVID-19 incidence, severity, or mortality. We are reviewing these data sets as part of the Partnership for Research in Occupational, Transport, Environmental COVID Transmission (PROTECT) initiative, which is part of the National COVID-19 Core Studies. In this report, we review the data sets available (including the key variables on occupation and potential confounders) for examining occupational differences in SARS-CoV-2 infection and COVID-19 incidence, severity and mortality. We also discuss the possible types of analyses of these data sets and the definitions of (occupational) exposure and outcomes. We conclude that none of these data sets are ideal, and all have various strengths and weaknesses. For example, mortality data suffer from problems of coding of COVID-19 deaths, and the deaths (in England and Wales) that have been referred to the coroner are unavailable. On the other hand, testing data is heavily biased in some periods (particularly the first wave) because some occupations (e.g. healthcare workers) were tested more often than the general population. Random population surveys are, in principle, ideal for estimating population prevalence and incidence, but are also affected by non-response. Thus, any analysis of the risks in a particular occupation or sector (e.g. transport), will require a careful analysis and triangulation of findings across the various available data sets.

Background: In December 2013, it was discovered that drinking water supplied to one third of the households in Ronneby, southern Sweden, was highly contaminated by PFAS (sum level >10,000 ng/L) originated from firefighting foams used at a nearby military airport. Objectives: To report serum PFAS levels of Ronneby residents participating in a biomonitoring program, and to describe the variation by age, sex and calendar period for residential exposure. In addition, a reference group living in a neighboring municipality without PFAS contaminated drinking water was examined. Methods: Blood samples and demographic data were collected for 3297 Ronneby residents and 226 individuals from the reference group. Yearly residence addresses were available for 3086 Ronneby residents from the national population registry. Serum concentrations of PFHxS, PFOS and PFOA were determined in all participants, with additional PFHpA, PFNA and PFDA in subsets of the participants. Results: The population geometric means for serum PFHxS, PFOS and PFOA were 114, 135 and 6.8 ng/mL for all Ronneby residents, i.e.135, 35 and 4.5 times higher than for the reference group. Ronneby residents who resided in the area with contaminated water supply during 2005–2013 showed much higher PFAS levels in 2014 than those exposed only before 2005. Ronneby residents who never resided in the area with contaminated water supply also had higher serum PFAS levels than the reference group. All three PFAS were highly correlated (rs > 0.9 for each pair). Serum PFAS levels were lowest in teenage years and then increased with age. Adult females had lower PFAS levels on average than males under the age of 60 but higher above 60. Discussion: The results reveal high serum PFAS levels dominated by PFHxS and PFOS in the Ronneby residents highly exposed to PFAS originated from firefighting foams. The PFAS exposure in Ronneby permits studies of associations to a range of health parameters, as well as studies of the toxicokinetics of PFAS exposure.

Background: Residents of a large area of North-Eastern Italy were exposed for decades to high concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFAS) via drinking water. Serum PFAS levels have been consistently associated with elevated serum lipids, but few studies have been conducted among pregnant women, and none has stratified analyses by trimester of gestation. Elevated serum lipid levels during pregnancy can have both immediate and long-lasting effects on pregnant women and the developing fetus. We evaluated the association between perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluoro-hexanesulfonate (PFHxS) levels in relation to lipid profiles in highly-exposed pregnant women. Methods: A cross-sectional analysis was conducted in 319 pregnant women (age 14–48 years) enrolled in the Regional health surveillance program. Non-fasting blood samples were obtained in any trimester of pregnancy and analyzed for PFOA, PFOS and PFHxS, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C). Low-density lipoprotein cholesterol (LDL-C) was calculated. The associations between ln-transformed PFAS (and categorized into quartiles) and lipids were assessed using generalized additive models. Analyses were adjusted for potential confounders and stratified according to pregnancy trimester. Results: The geometric means of PFOA, PFOS and PFHxS were 14.78 ng/mL, 2.67 ng/mL and 1.89 ng/mL, respectively. The plasma levels of TC, HDL-C and LDL-C increased steadily throughout the trimesters. In the 1st trimester, PFOS was positively associated with TC and PFHxS with HDL-C. In the 3rd trimester, instead, an inverse relationship was seen between PFOA and PFHxS and both TC and LDL-C. Conclusions: Results suggest the associations between PFAS concentrations and lipid profiles in pregnant women might differ by trimesters of pregnancy. In the first trimester, patterns are similar to those of non-pregnant women, while they differ late in pregnancy. Different independent behavior of PFAS and lipid levels throughout the pregnancy might explain our observations. These findings support the ubiquitous exposure to PFAS and possible influence on lipid metabolisms during pregnancy and suggest a careful evaluation of the timing of PFAS measurement, when examining effects of PFAS during pregnancy on gestational outcomes related to serum lipids amounts.

Background: Perfluoroalkyl substances (PFAS) are widespread synthetic substances with various adverse health effects. A potential mechanism of toxicity for PFAS is via epigenetic changes, such as DNA methylation. However, few studies have evaluated associations between PFAS exposure and DNA methylation among adults, and data is especially scarce for women. Furthermore, exposure to environmental pollutants has been associated with epigenetic age acceleration, but no studies have yet evaluated whether PFAS is associated with epigenetic age acceleration. Objectives: To investigate whether exposure to PFAS is associated with alteration of DNA methylation and epigenetic age acceleration among women. Methods: In this observational pilot study, 59 women (aged 20–47 years at enrollment in 2014) from Ronneby, Sweden, an area with historically high PFAS exposure due to local drinking water contamination, were divided into three PFAS exposure groups (low, medium, and high). Genome-wide methylation of whole-blood DNA was analyzed using the Infinium MethylationEPIC BeadChip. Ingenuity Pathway Analysis was used for in silico functional assessment. Epigenetic age acceleration was derived from the DNA methylation data using Horvath’s epigenetic skin and blood clock. Results: 117 differentially methylated positions (q

Background: Residents of a large area of the Veneto Region (North-Eastern Italy) were exposed for decades to drinking water contaminated by perfluoroalkyl substances (PFAS). PFAS have been consistently associated with raised serum lipids, mainly in cross-sectional studies and in background exposure contexts, but the shape of the dose-response relationships has been poorly investigated. The objectives of our study were to evaluate the association between serum PFAS and serum lipids and their dose-response patterns in a large exposed population. Methods: A cross-sectional study was conducted in 16,224 individuals aged 20–39 years recruited in the regional health surveillance program. 15,720 subjects were analysed after excluding pregnant women (n = 327), participants reporting use of cholesterol lowering medications (n = 67) or with missing information on the selected covariates (n = 110). Twelve PFAS were measured by HPLC-MS in serum; three (PFOA, PFOS and PFHxS) were quantifiable in at least 50% of samples. Non-fasting serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides were measured by enzymatic assays in automated analysers and low-density lipoprotein cholesterol (LDL-C), non-HDL cholesterol and total/HDL cholesterol ratio were calculated. The associations between natural log (ln) transformed PFAS and lipids were assessed through generalized additive models using linear regression and smoothing thin plate splines, adjusted for potential confounders. Results: There were strong positive associations between the ln-transformed PFOA, PFOS, and PFHxS and TC, HDL-C, and LDL-C, and between ln PFOA and PFHxS and triglycerides. Each ln-increase in PFOA was associated with an increase of 1.94 mg/dL (95% CI 1.48–2.41) in TC, with 4.99 mg/dL (CI 4.12–5.86) for PFOS and 2.02 mg/dL (CI 1.45–2.58) for PFHxS. Conclusions: Investigation of the shape of exposure-response associations using splines showed a positive association with the largest increases per unit of PFAS in cholesterol levels occurring at the lower range of PFAS concentrations for each compound.

Background: The C8 Science Panel was composed of three epidemiologists charged with studying the possible health effects of PFOA in a highly exposed population in the mid-Ohio Valley. The Panel determined in 2012 there was a ‘probable link’ (i.e., more probable than not based on the weight of the available scientific evidence) between PFOA and high cholesterol, thyroid disease, kidney and testicular cancer, pregnancy-induced hypertension, and ulcerative colitis. Objective: Here, former C8 Science Panel members and collaborators comment on the PFOA literature regarding thyroid disorders, cancer, immune and auto-immune disorders, liver disease, hypercholesterolemia, reproductive outcomes, neurotoxicity, and kidney disease. We also discuss developments regarding fate and transport, and pharmacokinetic models, and discuss causality assessment in cross-sectional associations among low-exposed populations. Discussion: For cancer, the epidemiologic evidence remains supportive but not definitive for kidney and testicular cancers. There is consistent evidence of a positive association between PFOA and cholesterol, but no evidence of an association with heart disease. There is evidence for an association with ulcerative colitis, but not for other auto-immune diseases. There is good evidence that PFOA is associated with immune response, but uneven evidence for an association with infectious disease. The evidence for an association between PFOA and thyroid and kidney disease is suggestive but uneven. There is evidence of an association with liver enzymes, but not with liver disease. There is little evidence of an association with neurotoxicity. Suggested reductions in birthweight may be due to reverse causality and/or confounding. Fate and transport models and pharmacokinetic models remain central to estimating past exposure for new cohorts, but are difficult to develop without good historical data on emissions of PFOA into the environment. Conclusion: Overall, the epidemiologic evidence remains limited. For a few outcomes there has been some replication of our earlier findings. More longitudinal research is needed in large populations with large exposure contrasts. Additional cross-sectional studies of low exposed populations may be less informative.

Abstract EFSA requested its Scientific Committee to prepare a guidance document on appraising and integrating evidence from epidemiological studies for use in EFSA's scientific assessments. The guidance document provides an introduction to epidemiological studies and illustrates the typical biases of the different epidemiological study designs. It describes key epidemiological concepts relevant for evidence appraisal. Regarding study reliability, measures of association, exposure assessment, statistical inferences, systematic error and effect modification are explained. Regarding study relevance, the guidance describes the concept of external validity. The principles of appraising epidemiological studies are illustrated, and an overview of Risk of Bias (RoB) tools is given. A decision tree is developed to assist in the selection of the appropriate Risk of Bias tool, depending on study question, population and design. The customisation of the study appraisal process is explained, detailing the use of RoB tools and assessing the risk of bias in the body of evidence. Several examples of appraising experimental and observational studies using a Risk of Bias tool are annexed to the document to illustrate the application of the approach. This document constitutes a draft that will be applied in EFSA's assessments during a 1‐year pilot phase and be revised and complemented as necessary. Before finalisation of the document, a public consultation will be launched.

Risk for renal cell carcinoma (RCC) is higher when there are first-degree family members with the disease. Here, Scelo and colleagues perform a genome-wide association meta-analysis and new genome-wide scan to identify seven new loci with significant RCC association.

Introduction: Thyroid hormones (THs) are especially important for brain maturation and development during the fetal period and childhood. Several epidemiological studies have assessed the possible association between exposure to perfluoroalkyl substances (PFAS) and thyroid outcomes during the early stages of life. We aimed to review this evidence. Methods: We conducted a systematic review in compliance with the PRISMA Statement (search conducted in PubMed and Embase, as well as in the citations of the selected articles). We chose studies if they dealt with thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxin (T4), or thyroid dysfunctions, and perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) or perfluorononanoic acid (PFNA) measured in the blood of pregnant women and/or children up to 19 years old. Results: We included in this review three cross-sectional, one case-control, and six cohort studies (publication: 2011–2015), focusing on prenatal life (n = 7), childhood (n = 2) or both periods (n = 1). We observed a high degree of heterogeneity across studies in terms of sampling time (different gestational weeks, at birth, or childhood), outcomes, adjustment for potential confounders, and statistical approach. We found some evidence of a positive association between PFHxS and PFOS exposure and TSH levels measured in maternal blood, and PFNA and TSH levels measured in the blood of boys aged ≥11 years. Conclusion: Although there is a small number of studies with comparable data, we found some consistency of a positive association between maternal or teenage male exposure to some PFAS and TSH levels based on the current literature. However, further studies are required to confirm these possible relationships. Keywords: Prenatal and infant exposure, Perfluorohexane sulfonate (PFHxS), Perfluorooctane sulfonate (PFOS), Perfluorooctanoic acid (PFOA), Perfluorononanoic acid (PFNA), Thyroid

BackgroundSeveral obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findingsGenetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.ConclusionsThis study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.