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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-GV GenPop ) 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode of action is based on blocking the activity of succinate dehydrogenase (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH is involved in two interconnected metabolic processes for energy production: the transfer of electrons in the mitochondrial respiratory chain and the oxidation of succinate to fumarate in the Krebs cycle. In humans, inherited SDH deficiencies may cause major pathologies including encephalopathies and cancers. The cellular and molecular mechanisms related to such genetic inactivation have been well described in neuroendocrine tumors, in which it induces an oxidative stress, a pseudohypoxic phenotype, a metabolic, epigenetic and transcriptomic remodeling, and alterations in the migration and invasion capacities of cancer cells, in connection with the accumulation of succinate, an oncometabolite, substrate of the SDH. We will discuss recent studies reporting toxic effects of SDHi in non-target organisms and their implications for risk assessment of pesticides. Recent data show that the SDH structure is highly conserved during evolution and that SDHi can inhibit SDH activity in mitochondria of non-target species, including humans. These observations suggest that SDHi are not specific inhibitors of fungal SDH. We hypothesize that SDHi could have toxic effects in other species, including humans. Moreover, the analysis of regulatory assessment reports shows that most SDHi induce tumors in animals without evidence of genotoxicity. Thus, these substances could have a non-genotoxic mechanism of carcinogenicity that still needs to be fully characterized and that could be related to SDH inhibition. The use of pesticides targeting mitochondrial enzymes encoded by tumor suppressor genes raises questions on the risk assessment framework of mitotoxic pesticides. The issue of SDHi fungicides is therefore a textbook case that highlights the urgent need for changes in regulatory assessment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Breast cancer (BC) is frequent with a poor prognosis in case of metastasis. The role of the environment has been poorly evaluated in its progression. We searched to assess whether a mixture of pollutants could be responsible of BC aggressiveness., Methods: Patients undergoing surgery for their BC were prospectively included in the METAPOP cohort. Forty-two POPs were extracted, among them 17 dioxins (PCDD/F), 16 polychlorobiphenyls (PCB), 8 polybromodiphenylethers (PBDE) and 2,2',4,4',5,5'-hexabromobiphenyl (PBB153) were measured in the adipose tissue surrounding the tumor. BC aggressiveness was defined using tumor size and metastasis (distant or lymph nodes). Two complementary models were used to evaluate the impact of the mixture of pollutants: the BKMR (Bayesian Kernel machine regression) and WQS (weighted quantile sum regression) models. The WQS estimates the weight (positive or negative) of a certain chemical based on its quantile and the BKMR model applies a kernel-based approach to estimate posterior inclusion probabilities. The sub-group of patients with a body mass index (BMI) > 22 kg/ m 2 was also analyzed., Results: Ninety-one patients were included. Of these, 38 patients presented a metastasis, and the mean tumor size was 25.4 mm. The mean BMI was 24.5 kg/m 2 (+/- 4.1). No statistical association was found in the general population. However, in patients with a BMI > 22 kg/ m 2 , our mixture was positively associated with tumor size (OR: 9.73 95 %CI: 1.30-18.15) and metastasis (OR = 3.98 95 %CI = 1.09-17.53) using the WQS model. Moreover, using the BKMR model on chemical families, dioxin like chemicals and PCDD were associated with a higher risk of metastasis., Discussion: These novel findings identified a mixture associated with breast cancer aggressiveness in patients with a BMI > 22 kg/ m 2 ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human biomonitoring (HBM) is a crucial approach for exposure assessment, as emphasised in the European Commission's Chemicals Strategy for Sustainability (CSS). HBM can help to improve chemical policies in five major key areas: (1) assessing internal and aggregate exposure in different target populations; 2) assessing exposure to chemicals across life stages; (3) assessing combined exposure to multiple chemicals (mixtures); (4) bridging regulatory silos on aggregate exposure; and (5) enhancing the effectiveness of risk management measures. In this strategy paper we propose a vision and a strategy for the use of HBM in chemical regulations and public health policy in Europe and beyond. We outline six strategic objectives and a roadmap to further strengthen HBM approaches and increase their implementation in the regulatory risk assessment of chemicals to enhance our understanding of exposure and health impacts, enabling timely and targeted policy interventions and risk management. These strategic objectives are: 1) further development of sampling strategies and sample preparation; 2) further development of chemical-analytical HBM methods; 3) improving harmonisation throughout the HBM research life cycle; 4) further development of quality control / quality assurance throughout the HBM research life cycle; 5) obtain sustained funding and reinforcement by legislation; and 6) extend target-specific communication with scientists, policymakers, citizens and other stakeholders. HBM approaches are essential in risk assessment to address scientific, regulatory and societal challenges. HBM requires full and strong support from the scientific and regulatory domain to reach its full potential in public and occupational health assessment and in regulatory decision-making., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The understanding of disease etiology and pathogenesis has radically changed as a consequence of the new challenges posed by climate change, environmental degradation and emerging infectious diseases. The awareness of the influence of distal causes (e.g. planetary changes at the roots of new pandemics), of the social environment and of early life exposures calls for innovative models of disease onset. Here we propose a scheme for the practice of epidemiology and toxicology that incorporates new recent advancements in both disciplines, under the general umbrella of the "exposome". The exposome approach to disease encompasses a lifecourse perspective from conception onwards, and the investigation of the role played by all exposures individuals undergo in their lives. These include social inequalities and psychosocial influences, in addition to chemical, biological and physical exposures. We stress the role played by social differences and inequalities in the course of life as an overarching factor that influences downstream layers (including behaviours). We show that the idea of "lifecourse exposome" is compatible with the current interpretation of Adverse Outcome Pathways in toxicology, and in fact we propose an extension of the concept towards "lifecourse Adverse Outcome Pathways". We propose to merge different research perspectives and promote an encounter between the sociological perspective of "biography" (using Pierre Bourdieu's conceptual framework) and biology, according to the idea of accumulated biological capital of individuals. We also propose to treat social capital (including inequalities) no longer as a confounding factor but as an overarching determinant, perhaps the most important of all because it is the one that influences all other exposures downstream. The importance of early exposures in a lifecourse perspective leads to policy implications, i.e. investing more in the various forms of capital (social, economic, cultural) in early life., (Copyright © 2022. Published by Elsevier Ltd.)

Adverse outcome pathways (AOPs) are formalized and structured linear concepts that connect one molecular initiating event (MIE) to an adverse outcome (AO) via different key events (KE) through key event relationships (KER). They are mainly used in eco-toxicology toxicology, and regulatory health issues. AOPs must respond to specific guidelines from the Organization for Economic Co-operation and Development (OECD) to weight the evidence between each KE. Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer related death (AO), through different KEs, constituting a new AOP. An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, angiogenesis, and invasion. These KEs promote an increased tumor growth, angiogenesis and migration which leads to breast cancer metastasis and breast cancer related death. The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines. The confidence in our AOP was considered strong. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer-related death with an innovative use of an artificial intelligence literature search., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The aim of the EU-funded HERA (health and environment research agenda) project is to set priorities for the future European research agenda in the environment, climate and health nexus. We report results from a European researcher's perspective and identify research areas that have been inadequately investigated to date., Methods: An online survey was completed by European researchers to assess, evaluate and visualise research gaps. These research gaps were identified for 21 predefined areas within 3 main categories: i) classical environment and health paradigm; ii) problem or sector-based research areas and approaches and iii) holistic research areas and concepts. All research gaps were then evaluated by expert groups with the pre-defined criteria and systematically summarized. For areas identified within the survey as under-reported, additional input was sought from a range of key selected experts. The EU project database Cordis was utilized to verify that these areas were under-researched., Results: Between May and July 2019, 318 respondents from 38 countries reported 624 research gaps. The main areas for attention identified were: urban environments; chemicals; and climate change, (combined n = 313 gaps). Biodiversity loss and health; transport, mobility, sustainable solutions and health; energy transition and health; waste and the circular economy and health; ethics and philosophy and health were areas that were acknowledged as under-researched (combined n = 27 gaps). These under-researched areas were identified as having certain commonalities, they: i) mostly fell in the category "problem or sector based approaches"; ii) they are essential for developing and implementing solutions; and iii) require trans-disciplinary and cross-sectoral collaboration., Conclusions: Currently attention is given to topical and highly researched areas in environmental health. In contrast, this paper identifies key topics and approaches that are under-researched, yet, are critical for the implementation of the EU Green Deal, related strategies and action plans, and require further investigation and investment. The findings reveal the imperative to foster solutions-oriented, trans-disciplinary and participatory research and its implementation through changes in research funding and research structures., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The implementation of One Health/EcoHealth/Planetary Health approaches has been identified as key (i) to address the strong interconnections between risk for pandemics, climate change and biodiversity loss and (ii) to develop and implement solutions to these interlinked crises. As a response to the multiple calls from scientists on that subject, we have here proposed seven long-term research questions regarding COVID-19 and emerging infectious diseases (EIDs) that are based on effective integration of environmental, ecological, evolutionary, and social sciences to better anticipate and mitigate EIDs. Research needs cover the social ecology of infectious disease agents, their evolution, the determinants of susceptibility of humans and animals to infections, and the human and ecological factors accelerating infectious disease emergence. For comprehensive investigation, they include the development of nature-based solutions to interlinked global planetary crises, addressing ethical and philosophical questions regarding the relationship of humans to nature and regarding transformative changes to safeguard the environment and human health. In support of this research, we propose the implementation of innovative multidisciplinary facilities embedded in social ecosystems locally: ecological health observatories and living laboratories. This work was carried out in the frame of the European Community project HERA (www.HERAresearchEU.eu), which aims to set priorities for an environment, climate and health research agenda in the European Union by adopting a systemic approach in the face of global environmental change., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients at high risk of severe forms of COVID-19 frequently suffer from chronic diseases, but other risk factors may also play a role. Environmental stressors, such as endocrine disrupting chemicals (EDCs), can contribute to certain chronic diseases and might aggravate the course of COVID-19., Objectives: To explore putative links between EDCs and COVID-19 severity, an integrative systems biology approach was constructed and applied., Methods: As a first step, relevant data sets were compiled from major data sources. Biological associations of major EDCs to proteins were extracted from the CompTox database. Associations between proteins and diseases known as important COVID-19 comorbidities were obtained from the GeneCards and DisGeNET databases. Based on these data, we developed a tripartite network (EDCs-proteins-diseases) and used it to identify proteins overlapping between the EDCs and the diseases. Signaling pathways for common proteins were then investigated by over-representation analysis., Results: We found several statistically significant pathways that may be dysregulated by EDCs and that may also be involved in COVID-19 severity. The Th17 and the AGE/RAGE signaling pathways were particularly promising., Conclusions: Pathways were identified as possible targets of EDCs and as contributors to COVID-19 severity, thereby highlighting possible links between exposure to environmental chemicals and disease development. This study also documents the application of computational systems biology methods as a relevant approach to increase the understanding of molecular mechanisms linking EDCs and human diseases, thereby contributing to toxicology prediction., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The holistic characterisation of the human internal chemical exposome using high-resolution mass spectrometry (HRMS) would be a step forward to investigate the environmental ætiology of chronic diseases with an unprecedented precision. HRMS-based methods are currently operational to reproducibly profile thousands of endogenous metabolites as well as externally-derived chemicals and their biotransformation products in a large number of biological samples from human cohorts. These approaches provide a solid ground for the discovery of unrecognised biomarkers of exposure and metabolic effects associated with many chronic diseases. Nevertheless, some limitations remain and have to be overcome so that chemical exposomics can provide unbiased detection of chemical exposures affecting disease susceptibility in epidemiological studies. Some of these limitations include (i) the lack of versatility of analytical techniques to capture the wide diversity of chemicals; (ii) the lack of analytical sensitivity that prevents the detection of exogenous (and endogenous) chemicals occurring at (ultra) trace levels from restricted sample amounts, and (iii) the lack of automation of the annotation/identification process. In this article, we discuss a number of technological and methodological limitations hindering applications of HRMS-based methods and propose initial steps to push towards a more comprehensive characterisation of the internal chemical exposome. We also discuss other challenges including the need for harmonisation and the difficulty inherent in assessing the dynamic nature of the internal chemical exposome, as well as the need for establishing a strong international collaboration, high level networking, and sustainable research infrastructure. A great amount of research, technological development and innovative bio-informatics tools are still needed to profile and characterise the "invisible" (not profiled), "hidden" (not detected) and "dark" (not annotated) components of the internal chemical exposome and concerted efforts across numerous research fields are paramount., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)