Centro Nacional de Sanidad Ambiental (CNSA)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19610

El Centro Nacional de Sanidad Ambiental (CNSA) es el órgano científico-técnico del Instituto de Salud Carlos III, especializado en los aspectos sanitarios de los problemas derivados de la contaminación medioambiental. Su finalidad primordial es la caracterización del riesgo potencial ante contaminantes ambientales a los que está expuesta la población. Fue creado mediante Decreto 252/1974, de 25 de enero y posteriormente, adscrito al Instituto de Salud Carlos III (Ley 14/1986). Sus laboratorios cuentan con una extensión de más de 3 000 m2, dotados con instrumentación de última tecnología. Funciona bajo un sistema de calidad UNE-EN ISO/IEC 17025 y está acreditado por la Entidad Nacional de Acreditación (ENAC) para 186 ensayos, distribuidos en las distintas unidades funcionales: Contaminación Atmosférica, Contaminación Hídrica y Microbiología Ambiental, Toxicología Ambiental y Radioprotección.

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Adolescent exposure to benzophenone ultraviolet filters: cross-sectional associations with obesity, cardiometabolic biomarkers, and asthma/allergy in six European biomonitoring studies.
(Elsevier, 2025-09-01) Peinado, Francisco M; Pérez-Cantero, Ainhoa; Olivas-Martínez, Alicia; Espín-Moreno, Lydia; de Haro, Tomás; Boada, Luis D; Rodríguez-Carrillo, Andrea; Govarts, Eva; Pedraza-Díaz, Susana; Esteban-Lopez, Marta; Blaha, Ludek; Blahova, Lucie; Janasik, Beata; Wasowicz, Wojciech; Lignell, Sanna; Rambaud, Loïc; Riou, Margaux; Fillol, Clémence; Denys, Sébastien; Murawski, Aline; Brantsæter, Anne Lise; Sakhi, Amrit Kaur; Iszatt, Nina; Schoeters, Greet; Kolossa-Gehring, Marike; Fernández, Mariana F; Mustieles, Vicente; Unión Europea. Comisión Europea. H2020; Ministerio de Agricultura, Pesca y Alimentación (España); Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública); The Research Council of Norway; Ministerio de Ciencia, Innovación y Universidades (España); Fundación Ramón Areces; Unión Europea. Fondo Social Europeo (ESF/FSE); Unión Europea. Comisión Europea. NextGenerationEU; Swedish Environmental Protection Agency; Swedish Civil Contingencies Agency; Swedish National Food Agency; Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (Deutschland); Federal Ministry of Education and Research (Deutschland); Norwegian Institute of Public Health
Background: Exposure to benzophenone-1 (BP-1) and benzophenone-3 (BP-3), widely used as UV filters in personal care products, has been associated with adverse health effects. However, epidemiological evidence is limited and inconclusive, particularly in vulnerable populations such as teenagers. Objective: To examine the relation between BP-1 and BP-3 concentrations and obesity, cardiometabolic biomarkers, and asthma/allergy outcomes in European teenagers, including possible sex-specific associations. Methods: A multi-country cross-sectional study was conducted using pooled data from six aligned studies from the Human Biomonitoring for Europe Initiative (HBM4EU). Sociodemographic data, cardiometabolic biomarkers, and asthma/allergy outcomes were collected through questionnaires. Anthropometric data and BMI z-scores were calculated (n = 1339). Plasma/serum cardiometabolic biomarkers and asthma/allergy outcomes were available for a subsample (n = 173-594). Urinary BP-1 and BP-3 concentrations were adjusted for creatinine dilution using the traditional standardization (trad.) and the covariate-adjusted creatinine standardization (CAS) method. Generalized additive models, linear, logistic, and multinomial mixed models were applied, and sex-interaction terms were tested. Results: Each natural log-unit increase in urinary BP-3 (CAS) concentrations was associated with higher odds of obesity in the whole population (OR: 1.20; 95%CI: 1.04-1.38). Sex-specific associations were also found with BP-1 (CAS) and BP-3 (CAS) concentrations, which were associated with higher odds of obesity in male teenagers (OR: 1.25; 95% CI: 1.01-1.55; OR: 1.34; 95%CI: 1.09-1.65, respectively). Linear mixed models showed consistent findings toward higher BMI z-scores. A negative association was found between BP-1 (CAS) concentration and serum adiponectin levels in females (% change per loge-unit increase: -3.73, 95%CI: -7.32, -0.10). BP-3 (CAS) concentrations were also associated with higher odds of non-food allergies in males (OR: 1.27; 95%CI: 1.00-1.63). Traditional creatinine adjustment showed similar or slightly attenuated estimates compared to the CAS method. Conclusions: BP-1 and BP-3 exposure was cross-sectionally associated with higher odds of obesity in European male teenagers, highlighting the need to update regulations and keep exposure levels as low as practically achievable. Longitudinal studies are needed to confirm these findings.
Human cerebral organoids: Complex, versatile, and human-relevant models of neural development and brain diseases.
(Wolters Kluwer, 2026-03-01) Coronel Lopez, Raquel; González-Sastre, Rosa; Mateos-Martínez, Patricia; Maeso Cuesta, Laura; Llorente-Beneyto, Elena; Martín-Benito, Sabela; Costa Gagosian, Viviana S; Foti, Leonardo; González-Caballero, MCarmen; López-Alonso, Victoria; Liste-Noya, Isabel; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España); Agencia Estatal de Investigación (España); Comunidad de Madrid (España)
The brain is the most complex human organ, and commonly used models, such as two-dimensional-cell cultures and animal brains, often lack the sophistication needed to accurately use in research. In this context, human cerebral organoids have emerged as valuable tools offering a more complex, versatile, and human-relevant system than traditional animal models, which are often unable to replicate the intricate architecture and functionality of the human brain. Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain, this field is currently under constant development, and work in this area is abundant. In this review, we give a complete overview of human cerebral organoids technology, starting from the different types of protocols that exist to generate different human cerebral organoids. We continue with the use of brain organoids for the study of brain pathologies, highlighting neurodevelopmental, psychiatric, neurodegenerative, brain tumor, and infectious diseases. Because of the potential value of human cerebral organoids, we describe their use in transplantation, drug screening, and toxicology assays. We also discuss the technologies available to study cell diversity and physiological characteristics of organoids. Finally, we summarize the limitations that currently exist in the field, such as the development of vasculature and microglia, and highlight some of the novel approaches being pursued through bioengineering.
A tiered next-generation risk assessment framework integrating toxicokinetics and NAM-based toxicodynamics: "proof of concept" case study using pyrethroids.
(Springer Nature, 2025-07) Fernandez Agudo, Ana; Tarazona, Jose; Unión Europea. Comisión Europea. Horizonte Europa
New Approach Methodologies (NAMs) in Next-Generation Risk Assessment (NGRA), integrating toxicokinetics (TK) with toxicodynamics (TD), provides an accurate evaluation of combined chemical exposures. This study assesses pyrethroids, which pose regulatory challenges due to their widespread use and cumulative exposure risks. A tiered NGRA framework was compared with conventional risk assessment (RA) to evaluate regulatory applicability. In Tier 1, ToxCast data established gene and tissue bioactivity indicators, facilitating hypothesis-driven hazard identification. Tier 2 examined combined risk assessments, rejecting the hypothesis of the same mode of action and highlighting inconsistencies in in vitro data and NOAEL/ADI correlations. Tier 3 applied Margin of Exposure (MoE) analysis and TK modeling to realistic exposure estimations for risk assessment screening based on internal doses, identifying tissue-specific pathways as critical risk drivers. Tier 4 refined bioactivity indicators using TK approaches to improve the NAM-based effect assessment, including an in vitro vs. in vivo comparison, with coherent results based on interstitial concentrations, though intracellular estimations remained uncertain. Tier 5 confirmed that dietary exposure in healthy adults is close to but below levels of concern, with bioactivity MoE values remaining below concern thresholds, and in vivo MoEs within the standard safety factors. Nevertheless, the MoEs are insufficient for addressing the additional non-dietary exposure expected from other pyrethroid uses such as biocides or pharmaceuticals. Results demonstrate that NGRA with TK-NAM-based TD offers a nuanced, regulatory-relevant framework for risk assessment. The proposed approach integrates the information on individual pyrethroids using bioactivity indicators; and the re-assessment of regulatory toxicity studies to select organ-relevant NOAELs allowed an improved in vitro-in vivo comparison, demonstrating the capacity of bioactivity-based MoEs for combined exposure assessments. This tiered approach provides key insights for regulatory decision-making, establishing a robust model for evaluating pyrethroids and similar chemical classes.
Sur8/Shoc2 como nuevo actor en envejecimiento y fragilidad (SENFRA-3). Data Management Plan V1.0.
(Instituto de Salud Carlos III (ISCIII). Centro Nacional de Sanidad Ambiental (CNSA), 2026-06-23) Briz, Víctor; Instituto de Salud Carlos III
Plan de Gestión de Datos del proyecto SENFRA-3. El proyecto globalmente es un esfuerzo colaborativo y multidisciplinar entre 5 Grupos del ISCIII que de forma cooperativa investigan un nuevo factor molecular que interviene en el envejecimiento. En estudios previos, se ha identificado el gen Sur8 como un factor clave en el envejecimiento celular. El proyecto, en su conjunto, pretende explorar el papel de Sur8 influye en los procesos de envejecimiento y fragilidad en múltiples organismos (mosca, ratón y gusano), incluidos los humanos. Dentro de la acción colaborativa conjunta, en este subproyecto (SENFRA-3) se pretende estudiar la ausencia de Sur8 en el cerebro de ratones modificados genéticamente para investigar su relación con el envejecimiento y la fragilidad combinando ensayos de conducta, de imagen y ómicos. En lo relativo al Plan de Gestión de Datos (PGD), este subproyecto es una investigación básica en la que los datos que se deriven del mismo, ya sean globales o individuales, son de tipo exploratorio y no son interpretables en términos de marcadores de fragilidad y envejecimiento o predicción de estos, sirviendo sólo de manera agregada para futuras investigaciones. El presente PGD establece las estrategias para garantizar la correcta generación, almacenamiento, acceso, difusión y protección de los datos científicos. Su objetivo principal es asegurar la calidad, integridad, trazabilidad y reutilización de la información, en línea con los principios de la ciencia abierta y la normativa ética vigente, y de acuerdo con las políticas institucionales del Instituto de Salud Carlos III.
High prevalence of azole resistance among environmental isolates from outdoor air in Madrid, Spain.
(Frontiers Media, 2026-01-23) Soto-Debrán, Juan Carlos; Sanchez Iñigo, Francisco Javier; Calvo-López, Alejandro B; Alguacil-Cuéllar, Laura; Hrynzovska, Anastasiia A; Mellado, Emilia; Garcia Dos Santos-Alves, Saul; Alastruey-Izquierdo, Ana; Instituto de Salud Carlos III
Introduction: Aspergillus fumigatus has been designated by the World Health Organization (WHO) as a critical fungal pathogen. Its spores are commonly present in the air and are inhaled daily. Azoles are the first-line treatment for Aspergillus infections, but the emergence of resistance is a growing concern. However, limited data exist on the occurrence of azole-resistant A. fumigatus in the outdoor environment in Spain. Methods: This study aimed to investigate the prevalence of azole-resistant A. fumigatus isolates in outdoor air at two distinct locations in Madrid. We characterized the isolates using TRESPERG genotyping and examined the underlying molecular mechanisms responsible for azole resistance development. Results: Azole-resistant A. fumigatus isolates were found in 55% of the 20 air samples collected. Among the 200 A. fumigatus isolates analyzed, 38.5% were azole resistant and were classified into 10 different genotypes. Notably, the TR34/L98H mutation in Cyp51A was found in 77% of the resistant isolates, while 23% showed no mutations in the screened targets (cyp51A, cyp51B, or hmg1). Discussion: This study revealed a high prevalence of azole-resistant A. fumigatus in outdoor environmental air, with the TR34/L98H mutation being the main mechanism of azole resistance. A close genetic relationship was observed among the resistant isolates. This research underscores the need for continued monitoring of environmental azole-resistant A. fumigatus isolates and highlights the importance of understanding genetic diversity and resistance mechanisms to develop effective strategies for fungal infection control.
Raw data for nanoplastic toxicity experiments in Daphnia magna: reproduction, morphology and behavior.
(Instituto de Salud Carlos III (ISCIII). Centro Nacional de Sanidad Ambiental (CNSA), 2026-03-24) Torres-Ruiz, Mónica
[EN] This project investigates the effects of polystyrene nanoplastics on aquatic organisms using Daphnia magna as a model, aiming to understand how individual-level exposure impacts key biological functions and may have broader ecological implications. [ES] Este proyecto investiga los efectos de nanoplásticos de poliestireno en organismos acuáticos utilizando Daphnia magna como modelo, con el objetivo de comprender cómo la exposición a nivel individual puede afectar funciones biológicas clave y tener implicaciones ecológicas.
Metodología científica y nuevas perspectivas de la evaluación de riesgos de sustancias químicas en sanidad ambiental.
(Instituto de Salud Carlos III (ISCIII). Centro Nacional de Sanidad Ambiental (CNSA), 2026-03) Domínguez-Morueco, Noelia; Fernandez Agudo, Ana; González-Caballero, MCarmen; Tarazona, Jose; Unidad de Evaluación de Riesgos, Centro Nacional de Sanidad Ambiental (CNSA)
Este libro surge para ofrecer una visión integrada y actualizada de la metodología científica aplicada a la evaluación de riesgos de sustancias químicas, abordando estos retos desde una perspectiva científica rigurosa, pero también práctica. Uno de sus principales valores, en línea con la ciencia de la evaluación de riesgos, es su enfoque multidisciplinar, que integra conocimientos procedentes de todos los ámbitos relacionados. Esta visión transversal refleja la realidad del trabajo en Sanidad Ambiental, donde la toma de decisiones exige una comprensión global de los procesos que vinculan las fuentes de contaminación, las vías de exposición, la toxicocinética de los químicos, los eventos tóxicos que se producen, la respuesta de cada organismo/ecosistema y en último término, los efectos sobre la salud humana y el medio ambiente, poniendo de manifiesto, la importancia de la evaluación de riesgos como instrumento clave para la toma de decisiones informadas y la formulación de políticas públicas eficaces. Por ello, confiamos en que se convierta en referencia para quienes trabajan, investigan y se forman en el ámbito de la Sanidad Ambiental, contribuyendo a mejorar la comprensión de los riesgos químicos y a reforzar las estrategias de prevención y protección de la salud.
Sensitive Instrumental Method for Quantitative Determination of High-Brominated Flame Retardants in Human Serum Samples
(Oxford University Press, 2023-05-12) Grande, Cristina; Castaño, Argelia; Ramos, Juan Jose
Background: High-brominated flame retardants (BFRs) can be released into the environment from consumer products, such as electric and electronic equipment, and enter the human body by different pathways. Because of their toxicity and the regulations, it is very relevant to know their levels and trends in human samples. However, chromatographic serum analysis of some of these compounds represents nowadays a challenge in the general population. Objective: To optimize and validate an instrumental method based on gas chromatography coupled to mass spectrometry, which, together with a simple sample preparation procedure, allows the analysis of decabromodiphenyl ether (BDE-209), decabromodiphenyl ethane (DBDPE), and tetrabromobisphenol A-bis(2,3-dibromopropyl ether) (TBBPA-DBPE) in human serum samples from the general population. Method: To minimize the high degradation during instrumental analysis, GC parameters such as injection volumes, carrier flow rates, and column lengths were assessed and optimized. This instrumental approach in combination with solid-phase extraction (SPE) followed by multilayer silica gel column purification allowed satisfactory analysis using only 1 mL of serum. Results: The performance of the complete method was evaluated at three spiking levels, 0.01, 0.05, and 0.2 ng/mL. Recoveries in the range 87-108% were obtained whereas the relative standard deviation in interday measurements, were, in general, lower than 19%. Limits of detection were in the range of 0.0045-0.0070 ng/mL. The optimized procedure was successfully applied to the determination of the investigated pollutants in real human samples of general population. Conclusions: The proposed method could contribute to the inclusion of these environmental pollutants in human biomonitoring (HBM) studies, increasing the knowledge of levels and trends in the general population. Highlights: GC-MS parameters optimization to minimize instrumental analytes degradation. Successful application to human serum samples from the general population. Tetrabromobisphenol A bis(2,3-dibromopropyl ether) human serum levels are reported for the first time.
Associations of internal persistent organic pollutant levels with sex hormones: An analysis by sex and menopausal status in a Spanish cohort
(Elsevier, 2025-07) Pérez-Díaz, Celia; Echeverría, Ruth; Pérez-Carrascosa, Francisco M.; Salcedo-Bellido, Inmaculada; Requena, Pilar; Barrios-Rodríguez, Rocío; Ramos, Juan Jose; Olea, Nicolás; Fernández, Mariana F.; Martín-Olmedo, Piedad; Arrebola, Juan Pedro
The aim of this study was to investigate associations between human exposure to persistent organic pollutants and sex hormone levels. The study population (n = 253) was a subsample of GraMo adult cohort, recruited in 2003-2004 in two hospitals from Granada, Spain. Exposure was estimated by analyzing samples of adipose tissue (3 organochlorine pesticides and 3 polychlorinated biphenyls) and serum (4 per- and polyfluoroalkyl substances). Data analyses included robust linear regression and weighted quantile sum regression. In men, PFNA (positively) and PCB-138 (negatively) were associated with testosterone. In premenopausal women, OCPs and PCBs were negatively associated with estradiol and SHBG. PFHxS was inversely related to luteinizing hormone. Additionally, PCB-153 and -180 was positively associated with testosterone. The mixture of PCBs/OCPs was positively associated with testosterone in women and with FSH in men. Our results highlight the potential of chemical mixture exposure to alter sex hormone homeostasis, depending on sex and menopausal status.
Urban Observatory for Multi-participatory Enhancement of Health and Wellbeing (URBANOME). Data Management Plan V2.0 (DMP)
(European Comission, 2023-02) Aristotle University of Thessaloniki (AUTH); University of Stuttgart (USTUT); Ambiente Italia (AMBIT); Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT); Robert Gordon University (RGU); Vilabs LTD (VIL); UPCOM BVBA; Institut Jozef Stefan (JSI); European Network of Living Labs IVZW (ENoLL); ADDMA; Aarhus Universitet (AU); Istituto Universitario di Studi Superiori ( I.U.S.S.) di Pavia; ENVE.X Single Member PC; Institut National de la Sante et de la Recherche Medicale (INSERM); Comune di Milano (CdM); Instituto de Salud Carlos III (ISCIII); Unión Europea. Comisión Europea. H2020
This document is the second version of the DMP (deliverable D10.3), delivered in Month 24 of the project. It includes updated information about the datasets produced by the project according to the FAIR principles to make the data findable, accessible, interoperable and reusable.
Partnership for the Assessment of Risks from Chemicals (PARC). Data Management Plan V1.0 (DMP)
(European Comission, 2022-10-31) van de Brug, Fred; Stierum, Rob; Partnership for the Assessment of Risks from Chemicals (PARC); Unión Europea. Comisión Europea. Horizonte Europa; Pedraza-Diaz, Susana, reviewer
PARC is the European partnership for the development of next generation chemical risk assessment methods. In the context of Open Science, the PARC objective OO10 is to implement FAIR data practices and enhance innovation in complex data analysis for chemicals risk assessment. PARC will develop a FAIR data culture enabling open science and provide the technical methods, tools and infrastructure for effective exchange of data and information. Innovation in risk assessment and risk management which is required for the transition to next generation risk assessment can only be achieved in an open and collaborative way. FAIR and open data sharing according to the ‘as open as possible, as closed as necessary’ principle will be the default for PARC and will be applied to all research outputs (including reports, data, software, guidelines, method descriptions, formats, templates, semantic artefacts, ontologies, vocabularies etc.). This deliverable presents version 1 of the PARC overarching data management plan (DMP). The domain specific guidance in version 1 is based on the analysis of DMP’s of a selection of projects covering research data domains PARC is concerned with: exposome research, biomonitoring, innovations in (eco-)toxicological hazard assessment, e.g., via in vitro new approach methodologies, nanomaterial safety and metabolism disrupting chemicals. The DMP contains guidance to support PARC researchers in multiple ways: by providing additional information; by providing generic texts and by suggesting possible domain specific or generic choices.
Emerging Pollutants in Chinstrap Penguins and Krill from Deception Island (South Shetland Islands, Antarctica)
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-06-29) Motas, Miguel; Jerez-Rodríguez, Silvia; Veiga-del-Baño, José Manuel; Ramos, Juan Jose; Oliva, José; Cámara, Miguel Ángel; Andreo-Martínez, Pedro; Corsolini, Simonetta; Ministerio de Ciencia e Innovación (España)
This study aimed to evaluate the presence of emerging pollutants [perfluorinated compounds, phthalates and bisphenol A (BPA)] in chinstrap penguins (Pygoscelis antarctica) and krill (Euphausia superba) from Deception Island (South Shetland Islands, Antarctica) to provide data on the occurrence of emerging pollutants in Antarctica. For this purpose, thirty-four samples were studied, including four samples of adult tissue and six samples of chick tissue, as well as krill samples from the area. The selected samples were subjected to extraction processes and subsequent analytical determination of perfluorooctane sulfonate, perfluorooctanoic acid, di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate and BPA using high-performance liquid chromatography coupled with electrospray ionization mass spectrometry. Our results highlight that the analyzed organic pollutants, except for BPA, are clearly present in Pygoscelis antarctica and Euphausia superba from Deception Island.
PCBs in Chinstrap Penguins from Deception Island (South Shetland Islands, Antarctica)
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-05-24) Motas, Miguel; Jerez-Rodríguez, Silvia; Veiga-Del-Baño, José Manuel; Ramos, Juan Jose; Oliva, José; Cámara, Miguel Ángel; Andreo-Martínez, Pedro; Corsolini, Simonetta; Ministerio de Ciencia e Innovación (España)
The aim of this study was to evaluate the concentration of polychlorinated biphenyls (PCBs) in chinstrap penguins (Pygoscelis antarctica) and krill (Euphausia superba) from Deception Island (South Shetland Islands, Antarctica) to provide additional data of the PCB presence in Antarctica. To this end, 34 samples of different tissues corresponding to four adult specimens and six chicks, and krill from the area were studied. The selected samples were analyzed for the determination of 27 congeners of PCBs by gas chromatography. Adult specimens accumulated PCBs mainly in the liver (33%, 1330.82 ± 733.69 pg·g-1 wet weight, w.w.) and muscle (25%, 1029.73 ± 823.4 pg·g-1 w.w.), whereas the brain showed the highest levels in chicks (36%, 1215.83 ± 955.19 pg·g-1 w.w.). Regarding krill, our results were five to eight times lower than the levels found in krill from King George Island and from the Ross Sea. Further, a distribution analysis of PCBs in penguins according to Regulation 2013/39/UE and Commission Regulation (EU) No 277/2012 was also performed, and PCBs were categorized into three groups (dioxin-like-mono-ortho, non-dioxin-like-indicators, and others-non-dioxin-like). The data indicate that the content of the other group was generally higher than that of the other two PCB groups for both adults and chicks. Notably, the liver consistently exhibited the highest proportion of the other group.
Short-Term Ozone Exposure and Daily Mortality in Suburban and Rural Areas of Southern Europe
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-05-20) Doronzo, Maria Angela; Martinez Fernandez, José Ramón; Gomez-Barroso, Diana; Alonso-Colón, María; Nuñez-Corcuera, Beatriz; Ramis, Rebeca; Unión Europea. Comisión Europea. H2020; Unión Europea. Comisión Europea. Horizonte Europa
Ozone (O3) is a major air pollutant with significant health effects, including increased respiratory and cardiovascular mortality. While previous research has largely focused on urban areas, this study assesses the association between maximum 8 h O3 concentrations and non-accidental mortality, including cardiovascular and respiratory mortality, in suburban and rural areas of Spain. We conducted a nationwide time-series analysis across 122 municipalities between April and September 2017 using Poisson regression models and adjusting for daily maximum temperature and provincial variability. Distributed lag models were applied to estimate the cumulative effects of ozone exposure on mortality, considering lags from 1 to 30 days. For each 10 µg/m3 increase in 8 h maximum O3 concentration, a significant increase in all-cause mortality risk of 2.3% was observed, with a peak at lag 2. Cardiovascular mortality increased by 2.4%, also peaking at lag 2, while respiratory mortality showed the strongest association, with a 4.3% rise at lag 1. A secondary mortality risk increase was observed at lags 24–28, suggesting the potential delayed effects of O3 exposure. These findings showed higher risk than those previously reported for urban populations and highlight the need for targeted public health interventions to mitigate the impact of ozone pollution in non-urban populations.
Calibration of Toenail Metal Concentrations for Sample Mass Heterogeneity and Between-Batch Variability: The COMET Approach
(National Institute of Environmental Health Sciences (NIEHS), 2025-04) Pastor-Barriuso, Roberto; Gutiérrez-González, Enrique; Varea-Jiménez, Elena; Gómez-Ariza, José Luis; Castaño-Vinyals, Gemma; Aragonés, Nuria; Molina, Antonio José; Dierssen-Sotos, Trinidad; Fernández-Tardón, Guillermo; Amiano, Pilar; Ederra-Sanz, María; Moreno, Victor; Jiménez-Moleón, José Juan; Molina-Barceló, Ana; Marcos-Gragera, Rafael; Casabonne, Delphine; Alguacil, Juan; Gómez-Gómez, Jesús Humberto; García-Barrera, Tamara; Kogevinas, Manolis; Pollan-Santamaria, Marina; Perez-Gomez, Beatriz; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública); Scientific Foundation
Background: Toenails are promising biomarkers of long-term metal exposure in epidemiological studies, but their accuracy may be compromised by systematic and random errors associated with heterogeneous toenail sample masses, as well as by substantial variability across laboratory batches. Objectives: We propose a novel modeling approach to calibrate toenail metal concentrations for the heterogeneity in sample masses and the variability between batches. Methods: We developed a heteroscedastic spline mixed model relating sample mass and laboratory batch with measured concentrations, allowing for an average bias in measurements over all batches as a smooth function of sample mass, random variation in mass-related biases across batches, and mass-related heterogeneity in within-batch error variance. The model allowed partitioning the total variance of measured concentrations into the extraneous variances (due to different sample masses and laboratory batches) and the intrinsic variance (resulting from distinct metal exposures). We derived calibrated metal concentrations from the model by removing both sources of extraneous variation and estimating the predicted concentrations had all toenail samples been analyzed in a single batch and of the same mass. We provide the R script COMET (COrrected METals) to fit the proposed model, extract variance components, and calibrate metal concentrations. Results: In a multicase-control study in Spain (MCC-Spain) with toenail determinations for 16 metals in 4,473 incident cases of five common cancers and 3,450 population controls, sample mass and batch accounted for 26%-60% of the total variance of measured concentrations for most metals. In comparison with calibrated concentrations, odds ratios for measured concentrations were biased by > 10% toward or away from the null in one-quarter of the estimated metal-cancer associations. Discussion: The proposed model allows correcting toenail metal concentrations for sample mass heterogeneity and between-batch variability and could be applied to other biological specimens of heterogeneous size, distinct laboratory techniques, and different study designs.
Different Ras isoforms regulate synaptic plasticity in opposite directions
(EMBO Press, 2025-02-21) López-Merino, Esperanza; Fernández-Rodrigo, Alba; Jiang, Jessie G; Gutiérrez-Eisman, Silvia; Fernández de Sevilla, David; Fernández-Medarde, Alberto; Santos, Eugenio; Guerra, Carmen; Barbacid, Mariano; Esteban, José A; Briz, Víctor; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Fundación Ramón Areces; Ministerio de Ciencia (España)
The small GTPase Ras is an intracellular signaling hub required for long-term potentiation (LTP) in the hippocampus and for memory formation. Genetic alterations in Ras signaling (i.e., RASopathies) are linked to cognitive disorders in humans. However, it remains unclear how Ras controls synaptic plasticity, and whether different Ras isoforms play overlapping or distinct roles in neurons. Using genetically modified mice, we show here that H-Ras (the most abundant isoform in the brain) does not promote LTP, but instead long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). Mechanistically, H-Ras is activated locally in spines during mGluR-LTD via c-Src, and is required to trigger Erk activation and de novo protein synthesis. Furthermore, H-Ras deletion impairs object recognition as well as social and spatial memory. Conversely, K-Ras is the isoform specifically required for LTP. This functional specialization correlates with a differential synaptic distribution of the two isoforms H-Ras and K-Ras, which may have important implications for RASopathies and cognitive function.
Particulate Matter Exposure during Pregnancy and Childhood Leukemia Incidence
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-06-24) Sanz Olea, Enrique; Ojeda Sánchez, Carlos; Guxens, Mònica; Cañete, Adela; Pardo Romaguera, Elena; Gomez-Barroso, Diana; García-Pérez, Javier; Nuñez-Corcuera, Beatriz; Ortega-García, Juan Antonio; Ramis, Rebeca; Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública)
Leukemia is the most common childhood cancer and its etiology could be related to various environmental contaminants such as particulate matter (PM). The objective of our study is to evaluate the potential association between exposure to PM during pregnancy and the incidence of childhood leukemia. We established a population-based nationwide cohort using the Spanish Birth Registry Statistics database of the National Statistics Institute. We used spatiotemporal land use random forest models to estimate the concentrations of PM10 and PM2.5 for the entire pregnancy and by trimesters. We conducted logistic regression analyses adjusted for various covariates. In addition, we fitted generalized additive models (GAMs) to estimate the non-linear relationship between PM levels and leukemia incidence. The study included 3,112,123 children and 1066 cases of leukemia. The results for the continuous variable of PM10 exposure levels suggested an increased risk of childhood leukemia to be associated with higher exposure. The results for the categorized PM10 variable suggest an increased risk of childhood leukemia among pregnant women whose exposure levels were higher than the median (third and fourth quartiles). The results for PM2.5 were weaker. We found association between exposure to PM10 during pregnancy and an increased risk of childhood leukemia. Our findings indicate that public health interventions should aim to reduce air pollution to lower the incidence of childhood leukemia.
Exposure to bisphenol A in European women from 2007 to 2014 using human biomonitoring data - The European Joint Programme HBM4EU
(Elsevier, 2024-08) Tagne-Fotso, Romuald; Riou, Margaux; Saoudi, Abdessattar; Zeghnoun, Abdelkrim; Frederiksen, Hanne; Berman, Tamar; Montazeri, Parisa; Andersson, Anna-Maria; Rodriguez-Martin, Laura; Åkesson, Agneta; Berglund, Marika; Biot, Pierre; Castaño, Argelia; Charles, Marie-Aline; Cocco, Emmanuelle; Den Hond, Elly; Dewolf, Marie-Christine; Esteban-Lopez, Marta; Gilles, Liese; Govarts, Eva; Guignard, Cedric; Gutleb, Arno C; Hartmann, Christina; Kold Jensen, Tina; Koppen, Gudrun; Kosjek, Tina; Lambrechts, Nathalie; McEachan, Rosemary; Sakhi, Amrit K; Snoj Tratnik, Janja; Uhl, Maria; Urquiza, Jose; Vafeiadi, Marina; Van Nieuwenhuyse, An; Vrijheid, Martine; Weber, Till; Zaros, Cécile; Tarroja-Aulina, Elena; Knudsen, Lisbeth E; Covaci, Adrian; Barouki, Robert; Kolossa-Gehring, Marike; Schoeters, Greet; Denys, Sebastien; Fillol, Clémence; Rambaud, Loïc; Unión Europea. Comisión Europea. H2020; Wellcome Trust; Medical Research Council (Reino Unido); Economic and Social Research Council (Reino Unido); British Heart Foundation; NIHR - Collaboration for Leadership in Applied Health Research and Care Yorkshire and Humber; Unión Europea. Comisión Europea. 7 Programa Marco; Department of Environment and Health (Bélgica); Instituto de Salud Carlos III; Ministerio de Agricultura, Alimentación y Medio Ambiente (España); Slovenian Research Agency; Luxembourg Institute of Science and Technology; Danish Ministry of Environment and Food; Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (Alemania); Ministère de la Santé (Francia); French National Agency of Research (Francia); Government of Catalonia (España); Ministry of Higher Education and Research (Francia); Federal Ministry of Agriculture, Forestry, Environment and Water Management (Austria); Austrian Federal Ministry of Health (Austria); Environment and Health Fund (Israel); Environment Agency Austria
Background: Bisphenol A (BPA; or 4,4'-isopropylidenediphenol) is an endocrine disrupting chemical. It was widely used in a variety of plastic-based manufactured products for several years. The European Food Safety Authority (EFSA) recently reduced the Tolerable Daily Intake (TDI) for BPA by 20,000 times due to concerns about immune-toxicity. Objective: We used human biomonitoring (HBM) data to investigate the general level of BPA exposure from 2007 to 2014 of European women aged 18-73 years (n = 4,226) and its determinants. Methods: Fifteen studies from 12 countries (Austria, Belgium, Denmark, France, Germany, Greece, Israel, Luxembourg, Slovenia, Spain, Sweden, and the United Kingdom) were included in the BPA Study protocol developed within the European Joint Programme HBM4EU. Seventy variables related to the BPA exposure were collected through a rigorous post-harmonization process. Linear mixed regression models were used to investigate the determinants of total urine BPA in the combined population. Results: Total BPA was quantified in 85-100 % of women in 14 out of 15 contributing studies. Only the Austrian PBAT study (Western Europe), which had a limit of quantification 2.5 to 25-fold higher than the other studies (LOQ=2.5 µg/L), found total BPA in less than 5 % of the urine samples analyzed. The geometric mean (GM) of total urine BPA ranged from 0.77 to 2.47 µg/L among the contributing studies. The lowest GM of total BPA was observed in France (Western Europe) from the ELFE subset (GM=0.77 µg/L (0.98 µg/g creatinine), n = 1741), and the highest levels were found in Belgium (Western Europe) and Greece (Southern Europe), from DEMOCOPHES (GM=2.47 µg/L (2.26 µg/g creatinine), n = 129) and HELIX-RHEA (GM=2.47 µg/L (2.44 µg/g creatinine), n = 194) subsets, respectively. One hundred percent of women in 14 out of 15 data collections in this study exceeded the health-based human biomonitoring guidance value for the general population (HBM-GVGenPop) of 0.0115 µg total BPA/L urine derived from the updated EFSA's BPA TDI. Variables related to the measurement of total urine BPA and those related to the main socio-demographic characteristics (age, height, weight, education, smoking status) were collected in almost all studies, while several variables related to BPA exposure factors were not gathered in most of the original studies (consumption of beverages contained in plastic bottles, consumption of canned food or beverages, consumption of food in contact with plastic packaging, use of plastic film or plastic containers for food, having a plastic floor covering in the house, use of thermal paper…). No clear determinants of total urine BPA concentrations among European women were found. A broader range of data planned for collection in the original questionnaires of the contributing studies would have resulted in a more thorough investigation of the determinants of BPA exposure in European women. Conclusion: This study highlights the urgent need for action to further reduce exposure to BPA to protect the population, as is already the case in the European Union. The study also underscores the importance of pre-harmonizing HBM design and data for producing comparable data and interpretable results at a European-wide level, and to increase HBM uptake by regulatory agencies.
Enhanced Risk Assessment of Transformation Products through Chemical Similarity Analysis
(ACS Publications, 2024-04-17) Löffler, Paul; Lai, Adelene; Henschel, Henning; Spilsbury, Francis; Deviller, Genevieve; Tarazona, Jose; Yin Lai, Foon; Swedish Research Council
Applicability of Food Monitoring Data for Assessing Relative Exposure Contributions of Pyrethroids in Retrospective Human Biomonitoring Risk Estimations
(Multidisciplinary Digital Publishing Institute (MDPI), 2024) De Alba-González, Mercedes; González-Caballero, MCarmen; Tarazona, Jose; Unión Europea. Comisión Europea. Horizonte Europa
The use of pyrethroids is very broad and shows increasing trends. Human biomonitoring studies represent the best approach for realistic risk estimations, but their interpretation requires a tiered approach. A previous HBM4EU study indicated levels in European children groups just around the threshold for concern, requiring further refinement. The main difficulty is that several pyrethroids with different toxicity potencies generate the same urinary metabolites. As diet is the main pyrethroid source for the general population, EU food monitoring data reported by EFSA have been used to estimate the relative contribution of each pyrethroid. The main contributors were cypermethrin for DCCA and 3-PBA and lambda-cyhalothrin for CFMP. Urinary levels predicted from food concentration according to the EFSA diets were mostly within the range of measured levels, except 3-PBA and CFMP levels in children, both below measured levels. The predicted lower levels for 3-PBA can be explained by the very low Fue value, initially proposed as conservative, but that seems to be unrealistic. The discrepancies for CFMP are mostly for the highest percentiles and require further assessments. The refined assessments included the revision of the previously proposed human biomonitoring guidance values for the general population, HBM-GV Gen Pop, following recent toxicological reevaluations, and the estimation of hazard quotients (HQs) for each individual pyrethroid and for the combined exposure to all pyrethroids. All HQs were below 1, indicating no immediate concern, but attention is required, particularly for children, with HQs in the range of 0.2-0.3 for the highly exposed group. The application of probabilistic methods offers assessments at the population level, addressing the variability in exposure and risk and providing relevant information for Public Health impact assessments and risk management prioritization.

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