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Humans are exposed to a large number of chemicals from sources such as the environment, food, and consumer products. There is growing concern that human exposure to chemical mixtures, especially during critical periods of development, increases the risk of adverse health effects in newborns or later in life. Historically, the onechemical-at-a-time approach has been applied both for exposure assessment and hazard characterisation, leading to insufficient knowledge about human health effects caused by exposure to mixtures of chemicals that have the same target. To circumvent this challenge researchers can apply in vitro assays to analyse both exposure to and human health effects of chemical mixtures in biological samples. The advantages of using in vitro assays are: (i) that an integrated effect is measured, taking combined mixture effects into account and (ii) that in vitro assays can reduce complexity in identification of Chemicals of Emerging Concern (CECs) in human tissues. We have reviewed the state-of-the-art on the use of receptor-based in vitro assays to assess human exposure to chemical mixtures and related health impacts. A total of 43 studies were identified, in which endpoints for the arylhydrocarbon receptor (AhR), the estrogen receptor (ER), and the androgen receptor (AR) were used. The majority of studies reported biological activities that could be associated with breast cancer incidence, male reproductive health effects, developmental toxicities, human demographic characteristics or lifestyle factors such as dietary patterns. A few studies used the bioactivities to check the coverage of the chemical analyses of the human samples, whereas in vitro assays have so far not regularly been used for identifying CECs in human samples, but rather in environmental matrices or food packaging materials. A huge field of novel applications using receptor-based in vitro assays for mixture toxicity assessment on human samples and effect-directed analysis (EDA) using high resolution mass spectrometry (HRMS) for identification of toxic compounds waits for exploration. In the future this could lead to a paradigm shift in the way we unravel adverse human health effects caused by chemical mixtures. ; European Union's Horizon 2020 research and innovation programme HBM4EU 733032

This paper presents an analysis of the opinions of different groups from: scientists, international regulatory bodies, non-governmental organizations and industry; with an interest in the problem of identifying chemical substances with endocrine disrupting activity. There is also discussion of the consequences that exposure to endocrine disruptors may have for human health, considering concrete issues related to: the estimation of risk; the tests that must be used to detect endocrine disruption; the difficulties to establish an association between dose, time of exposure, individual susceptibility, and effect; and the attempts to create a census of endocrine disruptors. Finally, it is proposed that not all hormonal mimics should be included under the single generic denomination of endocrine disruptors. ; This work was supported by a 96/99 Research Project from the Health Department of the Andalusian Regional Government.

This work was supported by the Ministry of economy and competitiveness and the National Institute of Health: Instituto de Salud Carlos III (ISCIII). Exps: PI14/00067, PI14/01716, PI14/01880, PI14/00556. BA15/00093. FFIS-CC 2016-06 AECC "Junta provincial de Murcia". FEDER and AECC 2015. Dr. J.P. Arrebola is under contract within Ramon y Cajal program (RYC-2016-20155, Ministerio de Economia, Industria y Competitividad, Spain). The EPIC-Spain cohort was supported by the Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII), the Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology -ICO (Spain). ; Background Bisphenol A (BPA) is an endocrine disruptor that it is present in numerous products of daily use. The aim of this study was to assess the potential association of serum BPA concentrations and the risk of incident breast and prostate cancer in a sub-cohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC). Methods We designed a case-cohort study within the EPIC-Spain cohort. Study population consisted on 4812 participants from 4 EPIC-Spain centers (547 breast cancer cases, 575 prostate cancer cases and 3690 sub-cohort participants). BPA exposure was assessed by means of chemical analyses of serum samples collected at recruitment. Borgan II weighted Cox regression was used to estimate hazard ratios. Results Median follow-up time in our study was 16.9 years. BPA geometric mean serum values of cases and sub-cohort were 1.12 ng/ml vs 1.10 ng/ml respectively for breast cancer and 1.33 ng/ml vs 1.29 ng/ml respectively for prostate cancer. When categorizing BPA into tertiles, a 40% increase in risk of prostate cancer for tertile 1 (p = 0.022), 37% increase for tertile 2 (p = 0.034) and 31% increase for tertile 3 (p = 0.072) was observed with respect to values bellow the limit of detection. No significant association was observed between BPA levels and breast cancer risk. Conclusions We found a similar percentage of detection of BPA among cases and sub-cohort from our population, and no association with breast cancer risk was observed. However, we found a higher risk of prostate cancer for the increase in serum BPA levels. Further investigation is needed to understand the influence of BPA in prostate cancer risk. ; Ministry of economy and competitiveness ; National Institute of Health: Instituto de Salud Carlos III (ISCIII) ; AECC "Junta provincial de Murcia" PI14/00067- PI14/01716- PI14/01880- PI14/00556- BA15/00093- FFIS-CC 2016-06 ; Spanish Government RYC-2016-20155 ; Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII) ; Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra ; Catalan Institute of Oncology -ICO (Spain)

The authors thank the European Union's Horizon 2020 research and innovation programme HBM4EU under Grant Agreement No. 733032 for its financial support. Vicente Mustieles and Stephan Couderq are under contract within the HBM4EU project. Additionally, we acknowledge the Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP), and the Instituto de Salud Carlos III (ISCIII) (FIS-PI16/01820 and FIS-PI16/01858). The authors also thank the ISCIII and "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) for the Sara Borrell postdoctoral research contract granted to F. Vela-Soria (grant no. CD17/00212), and the Spanish Ministry of Education for the predoctoral fellowship (FPU) granted to A. Rodríguez-Carrillo (FPU 16/03011). This article will be part of the doctoral thesis developed by Andrea Rodríguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain). The authors gratefully acknowledge the technical assistance of Birgitte Møller Plesning. ; Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on potential health effects, therefore improved tools for assessing these mixtures are needed. As part of the Human Bio-monitoring for Europe (HBM4EU) Project, we aimed to examine the combined biological activity of chemical mixtures extracted from human placentas using one in vivo and four in vitro bioassays, also known as biomarkers of combined effect. Relevant endocrine activities (proliferative and/or reporter gene assays) and four endpoints were tested: the estrogen receptor (ER), androgen receptor (AR), and aryl hydrocarbon receptor (AhR) activities, as well as thyroid hormone (TH) signaling. Correlations among bioassays and their functional shapes were evaluated. Results showed that all placental extracts agonized or antagonized at least three of the above-mentioned endpoints. Most placentas induced ER-mediated transactivation and ER-dependent cell proliferation, together with a strong ...

This work was reported in part at the meeting Estrogens in the Environment IV: Linking Fundamental Knowledge, Risk Assessment, and Public Policy held in Washington, DC, 19-21 July 1997. ; The chemical structure of hydroxylated diphenylalkanes or bisphenols consists of two phenolic rings joined together through a bridging carbon. This class of endocrine disruptors that mimic estrogens is widely used in industry, particularly in plastics. Bisphenol F, bisphenol A, fluorine-containing bisphenol A (bisphenol AF), and other diphenylalkanes were found to be estrogenic in a bioassay with MCF7 human breast cancer cells in culture (E-SCREEN assay). Bisphenols promoted cell proliferation and increased the synthesis and secretion of cell type-specific proteins. When ranked by proliferative potency, the longer the alkyl substituent at the bridging carbon, the lower the concentration needed for maximal cell yield; the most active compound contained two propyl chains at the bridging carbon. Bisphenols with two hydroxyl groups in the para position and an angular configuration are suitable for appropriate hydrogen bonding to the acceptor site of the estrogen receptor. Our data suggest that estrogenicity is influenced not only by the length of the substituents at the bridging carbon but also by their nature. Because diphenylalkane derivatives are widespread and their production and use are increasing, potential exposure of humans to estrogenic bisphenols is becoming a significant issue. The hazardous effects of inadvertent exposure to bisphenol-releasing chemicals in professional workers and the general populations therefore deserve investigation. ; This research was supported by grants from the Spanish Ministry of Health (FIS, 95/1959) and the Andalusian Regional Government Department of Health (Consejerla de Salud, 96/159).

'Reproduced with permission from Environmental Health Perspectives' ; Most of the composites and sealants used in dentistry are based on bisphenol A diglycidylether methacrylate (Bis-GMA). Reports revealed that in situ polymerization is not complete and that free monomers can be detected by different analytic methods. Concerns about the estrogenicity of bisphenol A (BPA) and other aromatic components leached from commercial products have been expressed. We studied biphenolic components eluted from seven composites and one sealant before and after in vitro polymerization using HPLC and gas chromatography/mass spectrometry and we investigated how pH modifications affect the leaching of these components. We found BPA (maximal amount 1.8 microg/mg dental material), its dimethacrylate derivative (Bis-DMA, 1.15 microg/mg), bisphenol A diglycidylether (6. 1 microg/mg), Bis-GMA (2.0 microg/mg), and ethoxylate and propoxylate of bisphenol A in media in which samples of different commercial products were maintained under controlled pH and temperature conditions. Our results confirm the leaching of estrogenic monomers into the environment by Bis-GMA-based composites and sealants in concentrations at which biologic effects have been demonstrated in in vivo experimental models. The main issue with implications for patient care and dentist responsibility is to further determine the clinical relevance of this estrogenic exposure. ; This research was supported by grants from the Spanish Ministry of Health (FIS, 95/1959) and Education (CICYT, AMB97-1194-CE) and the Andalusian Regional Government, Department of Health (Consejeria de Salud, JA, 231/97).

Bisphenol A (BPA) and its substitutes, bisphenol F (BPF) and S (BPS), have previously shown in vitro obesogenic activity. This study was designed to investigate their combined effect on the adipogenic differentiation of human adipose-derived stem cells (hASCs). Cells were exposed for 14 days to an equimolar mixture of bisphenols (MIX) (range 10 nM-10 mu M). Oil Red staining was used to measure intracellular lipid accumulation, quantitative real-time polymerase chain reaction (qRT-PCR) to study gene expression of adipogenic markers (PPAR gamma, C/EBP alpha, LPL, and FABP4), and Western Blot to determine their corresponding proteins. The MIX promoted intracellular lipid accumulation in a dose-dependent manner with a maximal response at 10 mu M. Co-incubation with pure antiestrogen (ICI 182,780) inhibited lipid accumulation, suggesting that the effect was mediated by the estrogen receptor. The MIX also significantly altered the expression of PPAR gamma, C/EBP alpha, LPL, and FABP4 markers, observing a non-monotonic (U-shaped) dose-response, with maximal gene expression at 10 nM and 10 mu M and lesser expression at 1 mu M. This pattern was not observed when bisphenols were tested individually. Exposure to MIX (1-10 mu M) also increased all encoded proteins except for FABP4, which showed no changes. Evaluation of the combined effect of relevant chemical mixtures is needed rather than single chemical testing. ; European Commission 733032 ; Biomedical Research Networking CenterCIBER de Epidemiologia y Salud Publica (CIBERESP) of the Institute of Health Carlos III European Commission FIS-PI16/01820 FIS-PI16/01812 FIS-PI16/01858 ; Spanish Government FPU 17/01848

The aim was to evaluate the associations of environmental phenol and paraben concentrations with the oxidative microenvironment in adipose tissue. This study was conducted in a subsample (n=144) of the GraMo cohort (Southern Spain). Concentrations of 9 phenols and 7 parabens, and levels of oxidative stress biomarkers were quantified in adipose tissue. Associations were estimated using multivariable linear regression analyses adjusted for potential confounders. Benzophenone-3 (BP-3) concentration was borderline associated with enhanced glutathione peroxidase (GPx) activity [exp(β)=1.20, p=0.060] and decreased levels of reduced glutathione (GSH) [exp(β)=0.55, p=0.070]. Concentrations of bisphenol A (BPA) and methylparaben (MeP) were associated to lower glutathione reductase (GRd) activity [exp(β)=0.83, exp(β)=0.72, respectively], and BPA was borderline associated to increased levels of oxidized glutathione (GSSG) [exp(β)=1.73, p-value=0.062]. MeP was inversely associated to both hemeoxygenase-1 (HO-1) and superoxide dismustase (SOD) activity, as well as to the levels of thiobarbituric acid reactive substances (TBARS) [0.75 < exp(β) < 0.79]. Our results suggest that some specific non-persistent pollutants may be associated with a disruption of the activity of relevant antioxidant enzymes, in addition to the depletion of the glutathione stock. They might act as a tissue-specific source of free radicals, contributing to the oxidative microenvironment in the adipose tissue. ; This research was supported in part by research grants from the European Union Commission (H2020-EJP-HBM4EU and SOE1/P1/F0082), Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP), from the Institute of Health Carlos III, supported by European Regional Development Fund/FEDER (FIS-PI13/02406, FISPI14/ 00067, FIS-PI16/01820, FIS-PI16/01812, FIS-PI16/01858 and FIS-PI17/01743), and from the Consejería de Salud, Junta de Andalucía (PS-0506-2016). Funding for the equipment used was provided by Velux Fonden, Augustinus Fonden and Svend Andersen Fonden. The authors thank Kirsten og Freddy Johansens Fond and the International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC, Rigshospitalet, Copenhagen University) for economic support. Dr. Juan Pedro Arrebola is under contract within Ramón y Cajal Program (Ministerio de Economía, Industria y Competitividad de España, RYC-2016-20155).

Objective: To characterize the exposure to electric fields and magnetic fields of non-ionizing radiation in the electromagnetic spectrum (15 Hz to 100 kHz) in the dwellings of children from the Spanish Environment and Childhood-"INMA" population-based birth cohort. Methodology: The study sample was drawn from the INMA-Granada cohort. Out of 300 boys participating in the 9–10 year follow-up, 123 families agreed to the exposure assessment at home and completed a specific ad hoc questionnaire gathering information on sources of non-ionizing radiation electric and magnetic fields inside the homes and on patterns of use. Long-term indoor measurements were carried out in the living room and bedroom. Results: Survey data showed a low exposure in the children's homes according to reference levels of the International Commission on Non-Ionizing Radiation Protection but with large differences among homes in mean and maximum values. Daytime electrostatic and magnetic fields were below the quantification limit in 78.6% (92 dwellings) and 92.3% (108 dwellings) of houses, with an arithmetic mean value (± standard deviation) of 7.31±9.32 V/m and 162.30±91.16 nT, respectively. Mean magnetic field values were 1.6 lower during the night than the day. Nocturnal electrostatic values were not measured. Exposure levels were influenced by the area of residence (higher values in urban/semi-urban versus rural areas), type of dwelling, age of dwelling, floor of the dwelling, and season. Conclusion: Given the greater sensitivity to extremely low-frequency electromagnetic fields of children and following the precautionary principle, preventive measures are warranted to reduce their exposure. ; This work was supported by the Spanish Ministry of Health (CIBERESP and FIS PI11/0610) and the Andalusia Regional Government, Council of Innovation, Science and Enterprise (Excellence Project P09-CTS-5488) and Council of Health (SAS PI-0675-2010).

Synthetic hormone-disrupting chemicals may play a role in the increased frequency of cryptorchidism observed in some studies. We used a spatial ecological design to search for variations in orchidopexy rates in the province of Granada in Spain and to search for relationships between these differences and geographical variations in exposure to pesticides. Orchidopexy rates were estimated for the period from 1980 to 1991 in all municipalities and health care districts served by the University of Granada Hospital. A random sample of males of the same age (1-16 years) admitted for any reason during the same period was used to estimate inpatient control rates. Each municipality was assigned to one of four levels of pesticide use. We used Poisson homogeneity tests to detect significant differences in rates of orchidopexy between districts and between levels of pesticide use. Poisson and logistic regression models were also used to estimate the strength of association between orchidopexy and level of pesticide use. Orchidopexy rates tended to be higher in districts near the Mediterranean coast where intensive farming is widespread. The city of Granada, where the reference hospital is located, also had higher figures both for orchidopexy and inpatient control rates. Regression models showed that the strength of association between orchidopexy and level of pesticide use tended to increase with higher levels of use, with the exception of level 0 (mainly in the city of Granada). Our results are compatible with a hypothetical association between exposure to hormone-disruptive chemicals and the induction of cryptorchidism. Several methodological limitations in the design make it necessary to evaluate the results with caution. ; This work was partially supported by the Health Council, Andalusian Regional Government through grant no. 94/556-140.

This research would not have been achieved without the selfless collaboration of the donors who took part in the study. The authors gratefully acknowledge editorial assistance from Richard Davies and the support of the "UNETE research unit" of the Centro de Investigacion Biomedica (University of Granada). This research was funded in part by grants from the European Union Commission (The European Human Biomonitoring Initiative H2020-EJP-HBM4EU), Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP), and the Carlos III Institute of Health (ISCIII) (PI16/01820, PI16/01812, PI16/01858, PI17/01743, and PI17/01526). The authors are also grateful to the ISCIII and the "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) for the predoctoral research contract granted to L.M. Iribarne-Duran (FI17/00316), the Sara Borrell postdoctoral research contract granted to F. Vela-Soria (grant no. CD17/00212), the Jose Maria Segovia de Arana contract granted to N. Olea (INT18/00060) and the Miguel Servet Type I Program granted to C. Freire (grant no. MS16/00085). This paper is part of the PhD thesis developed by Laura Serrano in the context of the "Clinical Medicine and Public Health Program" of the University of Granada. The funders had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. Funding for open access charge: University of Granada/CBUA. ; Background: Breast milk is considered to offer the best nutrition to infants; however, it may be a source of exposure to environmental chemicals such as perfluoroalkyl compounds (PFAS) for breastfeeding infants. PFAS are a complex group of synthetic chemicals whose high stability has led to their ubiquitous contamination of the environment. Objective: To assess the concentrations and profiles of PFAS in breast milk from donors to a human milk bank and explore factors potentially related to this exposure. Methods: Pooled milk samples were collected from 82 donors to the Human Milk Bank of the Virgen de las Nieves University Hospital (Granada, Spain). Ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) was applied to determine milk concentrations of 11 PFAS, including long-chain and short-chain compounds. A questionnaire was used to collect information on donors' socio-demographic characteristics, lifestyle, diet, and use of personal care products (PCPs). Factors related to individual and total PFAS concentrations were evaluated by multivariate regression analysis. Results: PFAS were detected in 24–100% of breast milk samples. PFHpA was detected in 100% of samples, followed by PFOA (84%), PFNA (71%), PFHxA (66%), and PFTrDA (62%). Perfluorooctane sulfonate (PFOS) was detected in only 34% of donors. The median concentrations ranged from <0.66 ng/dL (perfluorohexane sulfonic acid [PFHxS]) to 19.39 ng/L (PFHpA). The median of the sum of PFAS concentrations was 87.67 ng/L and was higher for short-chain than long-chain PFAS. Factors most frequently associated with increased PFAS concentrations included intake of creatin animal food items and use of PCPs such as skin care and makeup products. Conclusions: Several PFAS, including short-chain compounds, are detected in pooled donor milk samples. Breast milk may be an important pathway for the PFAS exposure of breastfed infants, including preterm infants in NICUs. Despite the reduced sample size, these data suggest that various lifestyle factors influence PFAS concentrations, highlighting the use of PCPs. ; "UNETE research unit" of the Centro de Investigacion Biomedica (University of Granada) ; European Union Commission (The European Human Biomonitoring Initiative H2020-EJP-HBM4EU) ; Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP) ; Instituto de Salud Carlos III PI16/01820 PI16/01812 PI16/01858 PI17/01743 PI17/01526 FI17/00316 CD17/00212 INT18/00060 MS16/00085 ; "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) FI17/00316 CD17/00212 INT18/00060 MS16/00085 ; University of Granada/CBUA

This research would not have been achieved without the selfless collaboration of the INMA-Granada adolescents and families who took part in the study. The authors acknowledge the European Union's Horizon 2020 research and innovation program HBM4EUfor the financial support under Grant Agreement #733032. The study was also supported by the ISCIII with grants no. CP16/00085 and FIS 17/01526, and the Human Genotyping Laboratory at the Spanish National Cancer Research Center (CeGen-PRB3). The authors also thank the support of the Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP), and the University of Granada (Grant "UNETE," UCE-PP2017-06). A. Rodriguez-Carrillo received a predoctoral fellowship (FPU 16/03011) from the Spanish Ministry of Education, Spain, and Vicente Mustieles and Shereen Cynthia D'Cruz were under contract with the HBM4EUproject. C. Freire received a grant under the Miguel Servet Type I program of the ISCIII "Fondo Europeo de Desarrollo Regional" (MS16/00085; ISCIII/FEDER). This article forms part of the doctoral thesis developed by Andrea Rodriguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain). ; Background: Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. Objectives: To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. Methods: The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide ...

Newborns in neonatal intensive care units (NICUs) are in contact with a variety of medical products whose production might include synthetic chemicals with hormonal activity. BPA was found in three-fifths and PBs in four-fifths of tested NICU items, and ∼25% and ∼10% of extracts evidenced estrogenic and anti-androgenic activity, respectively. The highest BPA content was found in the three-way stopcock (>7.000 ng/g), followed by patterned transparent film dressing, gastro-duodenal feeding tubes, sterile gloves, single-lumen umbilical catheters, and intravenous (IV) infusion extension sets (concentrations ranged from 100 to 700 ng/g BPA). A total PB concentration (∑PBs) >100 ng/g was observed in several items, including light therapy protection glasses, patterned transparent film dressing, winged IV catheters, IV infusion extension sets, and textile tape. The highest estrogenic activity [>450 pM estradiol equivalent (E2eq)] was found in small dummy nipples, three-way stopcocks, and patterned transparent film dressing and the highest anti-androgenic activity [>5 mM procymidone equivalent units per gram (Proceq/g)] in small dummy nipples and three-way stopcocks. According to these findings, neonates might be exposed to multiple sources of BPA and PBs in NICUs via inhalation, dermal, oral, and IV/parenteral routes. There is a need to address the future health implications for these extremely vulnerable patients and to adopt precautionary preventive measures as a matter of urgency. ; This research was funded in part by grants from the European Union Commission (The European Human Biomonitoring Initiative H2020-EJP-HBM4EU), the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III - FEDER (PI16/01820, PI16/01812, PI16/01858, PI17/01743, and PI17/01526), the Andalusia Regional Government (PI-0538-2017), and the Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP). The authors are also grateful to the Carlos III Institute of Health (ISCIII) for the predoctoral research contract (FI17/00316) granted to L.M.I.-D., the postdoctoral research contract granted to C.F. (Miguel Servet-FEDER fund MS16/00085), and the José María Segovia de Arana contract granted to N.O. (INT18/00060).

This paper is part of the PhD thesis developed by L.M.I.-D. in the context of the"Clinical Medicineand Public Health Program"of the University of Granada. ; BACKGROUND:Newborns in neonatal intensive care units (NICUs) are in contact with a variety of medical products whose production might includesynthetic chemicals with hormonal activity.OBJECTIVES:Our aim was to assess the content of bisphenol A (BPA) and parabens (PBs) and the hormone-like activities of a subset of medical prod-ucts commonly used in NICUs in prolonged intimate contact with NICU newborns.METHODS:Fifty-two NICU items were analyzed, determining the concentrations of BPA and PBs [methyl- (MeP), ethyl- (EtP), propyl- (PrP), andbutylparaben (BuP)] and using the E-Screen and PALM-luciferase assays to measure thein vitro(anti-)estrogenic and (anti-)androgenic activity,respectively, of the extracts. Items found to have elevated BPA/PB content or hormone-like activities were further extracted using leachingmethodologies.RESULTS:BPA was found in three-fifths and PBs in four-fifths of tested NICU items, and∼25%and∼10%of extracts evidenced estrogenic andanti-androgenic activity, respectively. The highest BPA content was found in the three-way stopcock (>7:000 ng=g), followed by patterned transpar-entfilm dressing, gastro-duodenal feeding tubes, sterile gloves, single-lumen umbilical catheters, and intravenous (IV) infusion extension sets (con-centrations ranged from 100 to 700 ng=g BPA). A total PB concentration (PPBs) >100 ng=g was observed in several items, including light therapyprotection glasses, patterned transparentfilm dressing, winged IV catheters, IV infusion extension sets, and textile tape. The highest estrogenic activ-ity [>450 pM estradiol equivalent (E2eq)] was found in small dummy nipples, three-way stopcocks, and patterned transparentfilm dressing and thehighest anti-androgenic activity [>5 mM procymidone equivalent units per gram (Proceq=g)] in small dummy nipples and three-way stopcocks ; This research was funded in part by grants from the European Union Commission (The European Human Biomonitoring Initiative H2020-EJP-HBM4EU), the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III - FEDER (PI16/01820, PI16/01812, PI16/01858, PI17/01743, and PI17/01526), the Andalusia Regional Government (PI-0538-2017), and the Spanish Consortium for Research on Epidemiology and Public Health(CIBERESP). The authors are also grateful to the Carlos IIIInstitute of Health (ISCIII) for the predoctoral research contract(FI17/00316) granted to L.M.I.-D., the postdoctoral researchcontract granted to C.F. (Miguel Servet-FEDER fund MS16/00085), and the José María Segovia de Arana contract granted to N.O. (INT18/00060).

Background: Little information is available on the content of bisphenol A (BPA) and other endocrine-disrupting chemicals (EDCs) such as parabens in infant textiles and clothes. Objectives: 1) To determine the concentrations of BPA and parabens in socks for infants and young children purchased in Spain, 2) to assess the (anti-)estrogenicity and (anti-)androgenicity of extracts from the socks, and 3) to estimate dermal exposure doses to these chemicals. Methods: Thirty-two pairs of socks for infants and young children (1–48 months) were purchased from 3 stores in Granada (Spain). Textile material was cut from the foot, toe, and leg of each sock (n=96 samples) for chemical analysis. Hormone-like activities were determined in foot sections (n=32 samples) by using the E-Screen assay for (anti-)estrogenicity and PALM luciferase assay for (anti-)androgenicity. Results: BPA was present in 90.6% of samples at concentrations ranging from<0.70 to 3736 ng/g. BPA levels were around 25-fold higher in socks from store 1, which had a higher cotton content compared to stores 2 and 3. Ethyl-paraben was found in 100% of samples, followed by methyl-paraben (81.0%), and propyl-paraben (43.7%). No butyl-paraben was detected in any sample. Estrogenic activity was detected in 83.3% of socks from store 1 (range=48.2–6051 pM E2eq/g) but in only three socks from stores 2 and 3. Anti-androgenic activity was detected in six of the 32 socks studied (range=94.4–2989 μM Proceq/g), all from store 1. Estimated dermal exposure to BPA was higher from socks for children aged 36–48 months (median=17.6 pg/kg/day), and dermal exposure to parabens was higher from socks for children aged 24–36 months (median=0.60 pg/kg/day). Discussion: This is the first report in Europe on the wide presence of BPA and parabens in socks marketed for infants and children. BPA appears to contribute to the hormone-like activity observed in sock extracts. ; This research was funded in part by grants from the European Union Commission (The European Human Biomonitoring ...