Analytical methods and biomonitoring results in hair for the assessment of exposure to endocrine-disrupting chemicals: A literature review.

Endocrine-disrupting chemicals (EDC) are compounds that alter functions of the endocrine system due to their ability to mimic or antagonize endogenous hormones, or that alter their synthesis and metabolism, causing adverse health effects. Human biomonitoring (HBM) is a reliable method to assess human exposure to chemicals through measurement in human body fluids and tissues. It identifies new sources of exposure and determines their distribution, thereby enabling detection of the most exposed populations. Blood and urine are commonly used for HBM of EDC, but their interest is limited for compounds presenting short half-lives. Hair appears as an interesting alternative insofar as it provides a large exposure window. For the present study, we evaluated the relevance of hair in determining EDC exposure. With this in mind, we undertook a literature review focusing on the bioanalytical aspects and performances of methods developed to determine EDC in hair. The literature review was performed through methodical bibliographical research. Relevant articles were identified using two scientific databases: PubMed and Web of Science, with search equations built from a combination of keywords, MeSH terms and Boolean operators. The search strategy identified 2949 articles. After duplicates were removed, and following title, abstract, and full-text screenings, only 31 were included for qualitative synthesis. Hair collection was mainly performed in the back of the head and preparation involved two processes: cutting into small pieces or grounding to powder. The off-line LC-MS/MS method remains the main technique used to assess EDC through hair. Differences regarding the validation of analytical methods and interpretation of HBM results were highlighted, suggesting a need for international harmonisation to obtain reliable and comparable results. External contamination of hair was identified as a main limitation in the interpretation of results, highlighting the need to better understand EDC transfers through hair and to develop relevant hair decontamination processes.

Therapeutic drug monitoring and virological response at week 48 in a cohort of HIV-1-infected patients switching to dolutegravir/rilpivirine dual maintenance therapy (ANRS-MIE-BIRIDER study).

AIMS: Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV-1 RNA viral load (VL) during maintenance dual therapy. METHODS: We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study. RESULTS: At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow-up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P = .015). CONCLUSION: A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin.

Assessment of Endocrine Disruptor Exposure in Hospital Professionals Using Hair and Urine Analyses: An Awareness Campaign.

BACKGROUND: In 2021, French public authorities initiated the fourth National Environmental Health Plan to prevent environment-related health risks. This plan primarily focuses on the sensitization of health professionals and health care institutions. Endocrine disruptors (EDs) are environmental factors associated with several adverse health effects, such as reproductive disorders, obesity, and cancer. This study aimed to conduct an awareness campaign among professionals at a general hospital center on the risks related to EDs. METHODS: Hospital professionals were directly involved in this study, and urine and hair samples were collected to determine bisphenol and paraben exposure levels. Analyses were performed using validated liquid chromatography-tandem mass spectrometry methods, enabling the simultaneous determination of bisphenols and parabens. A questionnaire on lifestyle habits was distributed to assess its relationship with the exposure profiles. Nineteen professionals were recruited for the study. RESULTS: Bisphenol A was detected in 95% of the urine samples, and the chlorinated derivatives of bisphenol A were between 16% and 63%. parabens showed detection frequencies between 37% and 100%, and methylparaben was quantified at an average concentration of 0.45 ± 0.46 ng/mL. In hair samples, bisphenols A, F, and S were detected at 95%-100%, chlorinated derivatives of bisphenol A were detected at 37%-68%, and parabens were detected at 100%. CONCLUSIONS: This awareness campaign may encourage health care institutions to adopt a policy of reducing endocrine disruptor exposure among their patients and professionals, who could be educated regarding the risks associated with EDs. Conducting a multicenter study to refine the results herein and establish a dynamic to prevent endocrine disruptor and environmental risks in health care systems would be valuable.

Exposure to endocrine disruptors promotes biofilm formation and contributes to increased virulence of Pseudomonas aeruginosa.

Anthropogenic activities contribute to the spread of chemicals considered as endocrine disruptors (ED) in freshwater ecosystems. While several studies have reported interactions of EDs with organisms in those ecosystems, very few have assessed the effect of these compounds on pathogenic bacteria. Here we have evaluated the impact of five EDs found in aquatic resources on the virulence of human pathogen P. aeruginosa. ED concentrations in French aquatic resources of bisphenol A (BPA), dibutyl phthalate (DBP), ethylparaben (EP), methylparaben (MP) and triclosan (TCS) at mean molar concentration were 1.13, 3.58, 0.53, 0.69, and 0.81 nM respectively. No impact on bacterial growth was observed at EDs highest tested concentration. Swimming motility of P. aeruginosa decreased to 28.4% when exposed to EP at 100 µM. Swarming motility increased, with MP at 1 nM, 10 and 100 µM (1.5-fold); conversely, a decrease of 78.5%, with DBP at 100 µM was observed. Furthermore, exposure to 1 nM BPA, DBP and EP increased biofilm formation. P. aeruginosa adhesion to lung cells was two-fold higher upon exposure to 1 nM EP. We demonstrate that ED exposure may simultaneously decrease mobility and increase cell adhesion and biofilm formation, which may promote colonisation and establishment of the pathogen.

Characterization of pregnant women exposure to halogenated parabens and bisphenols through water consumption.

Exposure of pregnant women to endocrine disruptor compounds, such as parabens and bisphenol A is of concern for fetal transition. Their halogenated degradation products, mainly coming from water treatment plans, could be problematic as well, depending on their occurrence in drinking water in the first place. Thus, 25 halogenated compounds were synthesised in order to investigate 60 substances (Bisphenols, parabens and their degradation products) in 325 drinking water samples coming from a French cohort study of pregnant women. Analysis was performed by tandem mass spectrometry coupled to gas chromatography (GC-MS/MS) after SPE extraction and derivation of the contaminants. Results indicate that parabens (methylparaben, n-propylparaben, ethylparaben and n-butylparaben), bisphenols S, A and F, and their degradation product, 4-hydroxybenzoic acid, were detected up to several hundred ng/L in drinking water, with detection frequencies between 16% and 88%. Regarding halogenated degradation products, the highest detection frequencies were found for monochlorinated products (about 50% for 2-chlorobisphenol A), which were quantified up to several tens of ng/L. Such analytical approaches with broader spectrum of monitoring (i.e. chemical hazards and their degradation products) constitute in the beginning of a solution to exhaustively answer the questions related to the characterization of the human chemical exposome.

Quantification of the Conjugated Forms of Dichlorobisphenol A (3,3'-Cl 2 BPA) in Rat and Human Plasma Using HPLC-MS/MS.

BACKGROUND: Bisphenol A (BPA) is a ubiquitous contaminant that has endocrine-disrupting effects. Chlorinated derivatives of BPA are formed during chlorination of drinking water and have higher endocrine-disrupting activity. Dichlorobisphenol A (Cl 2 BPA) is the most abundant chlorinated BPA derivative found in several human biological matrices. Recent in vitro experiments have shown that Cl 2 BPA is metabolized in sulpho- and glucuro-conjugated compounds. To date, no assay has been developed to quantify the sulfo- and glucuro-conjugates of 3,3'-Cl 2 BPA (3,3'-Cl 2 BPA-S and 3,3'-Cl 2 BPA-G, respectively). METHODS: A high-performance liquid chromatography-tandem mass spectrometry assay for the determination of 3,3'-Cl 2 BPA conjugated forms in plasma samples was developed and validated according to the European Medicines Agency guidelines. Quantification was performed in the multiple reaction monitoring mode for all target analytes using a SCIEX 6500 + tandem mass spectrometer with an electrospray source operating in the negative ionization mode. Chromatographic separation was achieved using a C18 column maintained at 40°C and a binary mobile phase delivered in the gradient mode at a flow rate of 0.35 mL/min. Sample was prepared via simple precipitation using acetonitrile. The assay was validated and applied to rat and human plasma samples. RESULTS: Linearity was demonstrated over the range of 0.006-25 ng/mL for 3,3'-Cl 2 BPA-G and 0.391-100 ng/mL for 3,3'-Cl 2 BPA-S. Intraday and interday bias values were in the 95%-109% range, and the imprecision <9%. Internal standard corrected matrix effects were also investigated. This method enabled quantification of the conjugated forms of 3,3'-Cl 2 BPA in plasma samples. CONCLUSIONS: This is the first report on the development and validation of an analytical method for the quantification of 3,3'-Cl 2 BPA-G and 3,3'-Cl 2 BPA-S in the plasma matrix. This study is also the first report on the in vivo occurrence of these metabolites.

In vitro reciprocal interactions between yeasts from human cutaneous mycobiota and parabens used in cosmetics.

Parabens are substances with antifungal and antibacterial properties, suspected to be endocrine disruptors and widely used as preservatives in cosmetics. In this case, exposure to these compounds is mainly dermal and interactions may occur with skin components including cutaneous mycobiota. In this work, we have explored the in vitro reciprocal interactions between three parabens (methylparaben, ethylparaben, and propylparaben) and yeasts from the human cutaneous mycobiota (Candida parapsilosis, Cryptococcus uniguttulatus, and Rhodotorula mucilaginosa) by studying the effect of these parabens on fungal growth and the fungal ability to metabolize the tested compounds. Our results showed that, at the tested concentrations, the growth of three strains of C. parapsilosis was not influenced by the presence of parabens. Whereas, using the same parabens concentrations, growth of C. uniguttulatus and R. mucilaginosa was completely inhibited by ethylparaben since the first day of contact, whereas these same fungi were not sensitive to the two other parabens, even after seven days of incubation. The presence of a lamellar wall in these basidiomycete fungi as well as the physico-chemical properties of ethylparaben could explain this selective inhibition. Additionally, C. parapsilosis and R. mucilaginosa degraded 90% to 100% of propylparaben after seven days of incubation but had no effect on the other tested parabens. Thus, their enzymes seem to only degrade long chain parabens. In the same conditions, C. uniguttulatus did not degrade any paraben. This inability may be due to the absence of fungal enzymes able to degrade parabens or to the possible inaccessibility of intracellular enzymes due to the polysaccharide capsule. Our work has shown that parabens can act differently from one fungus to another within the cutaneous mycobiota. These preliminary results have evidenced that in vitro parabens, contained in cosmetic products, could be involved in the occurrence of a state of dysbiosis. The tested yeasts from the cutaneous mycobiota can also be involved in the degradation of parabens and thereby reduce, according to the produced metabolites and their activities, the risk of endocrine disruption they can induce.

Analytical method for the biomonitoring of bisphenols and parabens by liquid chromatography coupled to tandem mass spectrometry in human hair.

Bisphenols and parabens are endocrine disruptors families widely used in daily life. They are known to be linked to numerous pathologies such as reproductive disorders, obesity, breast cancer, hypertension and asthma. Biomonitoring is an essential tool for assessing population exposure to environmental pollutants. Blood and urine are the main matrices used in human biomonitoring. However, they are not suitable to evaluate long-term exposure to endocrine disruptors with a short elimination half-life such as parabens or phenols. Hair appears to be an interesting alternative matrix allowing a wide window of exposure due to an accumulation of xenobiotics during hair growth. This study presents the development and validation of a high-performance liquid chromatography coupled to tandem mass spectrometry for the simultaneous determination of bisphenol A, its chlorinated derivatives, bisphenol F, bisphenol S and parabens in human hair. An optimised sample preparation based on acidic hydrolysis followed by liquid-liquid extraction was performed, before an analysis by ultra-high performance liquid chromatography coupled to tandem mass spectrometry in multiple reaction monitoring mode. To validate the method, recognized bioanalytical guidelines were used and calibration and quality control samples were prepared in human hair samples. Linearities were over 0.996 in the whole range of concentrations. Trueness and precision were demonstrated for each target analyte with intra-day and inter-day bias values ranging from 86 % to 118 % and relative standard deviation values ranging from 0 % to 19 %. At the same time, limits of quantification were set at 0.25 ng/g for bisphenol A and parabens, 0.05 ng/g for bisphenols F and S and 0.00625 ng/g for the chlorinated derivatives of bisphenol A. This reliable method was applied to hair samples taken from hospital professionals and allowed the quantification of these endocrine disruptors in this population. Chlorinated derivatives of bisphenol A were quantified here in hair for the first time.

Impact of perinatal environmental health education intervention on exposure to endocrine disruptors during pregnancy-PREVED study: study protocol for a randomized controlled trial.

BACKGROUND: The suspected or actual effects on health of endocrine-disrupting chemicals (EDC) and their ubiquitous presence in everyday life justify the implementation of health promotion interventions. These interventions should ideally be applied during critical windows like pregnancy. Perinatal environmental health education interventions may help to reduce EDC exposure during pregnancy. METHODS/DESIGN: PREVED (Pregnancy, PreVention, Endocrine Disruptors) is an open-label randomized controlled trial assessing the impact of environmental health education intervention on EDC exposure during pregnancy. Inclusion, consent, and randomization take place during the first trimester. The participants are randomly allocated into three groups: (i) control group (information leaflet on EDCs), (ii) intervention group in neutral location (information leaflet and workshops in a meeting room), and (iii) intervention group in contextualized location (information leaflet and workshops in a real apartment). Workshops are organized between the second and third trimesters of pregnancy. Main outcome is the percentage of participants who reported consuming manufactured/industrial food. Secondary outcomes are as follows: (i) psycho-social dimensions, (ii) EDC concentrations in urine, (iii) EDC concentration in colostrum, and (iv) percentage of participants who reported consuming paraben-free personal care products. DISCUSSION: PREVED is a ground-breaking intervention research project dedicated to perinatal environmental health education that aims to identify pollutant sources in daily life and to offer accessible and realistic alternative solutions, by promoting the sharing of know-how and experience in a positive and non-alarmist approach. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03233984 (current status: ongoing). Retrospectively registered on 31 July 2017 ( https://clinicaltrials.gov/ct2/show/NCT03233984 ) because when the first participant was enrolled in this non-drug intervention, ClinicalTrials.gov was centered in therapeutic trials. The World Health Organization Trial Registration Data Set is in Additional file 1.

Perinatal Environmental Health Education Intervention to Reduce Exposure to Endocrine Disruptors: The PREVED Project.

Environmental health promotion interventions may reduce endocrine disruptor (ED) exposure. The PREVED (PREgnancy, preVention, Endocrine Disruptors) project was developed to improve knowledge, to enhance risk perception, and to change exposure behavior. Our objective was to present the phases of the PREVED project using the RE-AIM method. PREVED intervention consisted of three workshops during pregnancy. Reach, adoption, and implementation phases were assessed with qualitative studies. Efficacy study consisted of a three-arm randomized controlled trial (RCT) on 268 pregnant women: (i) control group (leaflet), (ii) intervention group in neutral location, (iii) intervention group in contextualized location. The main outcome was the percentage evolution of participants who reported consuming canned food. Secondary outcomes were evolution of psycho-social scores, evolution of ED presence in urine, and ED presence in colostrum. The intervention adoption was centered on upper-privileged women, but implementation assessment showed that key features (highly practical intervention) seemed to be carried out and had initiated some behavior changes. A total of 268 pregnant women participated in the intervention and 230 in a randomized controlled trial (control group: 86 and intervention groups: 172). We found no significant differences in consumption of canned food and in percentage of women having a decrease of bisphenol A or parabens in urine, but we found a significant increase in the evolution of risk perception score and overall psychosocial score in intervention groups (respectively: +15.73 control versus +21.03 intervention, p = 0.003 and +12.39 versus +16.20, p = 0.02). We found a significant difference in percentage of women with butylparaben detection between control group and intervention groups (13% versus 3%, p = 0.03). PREVED intervention is the first intervention research dedicated to perinatal environmental health education in France. By sharing know-how/experience in a positive non-alarmist approach, it improved risk perception, which is key to behavior change, aiming to reduce perinatal ED exposure. Including women in precarious situations remains a major issue.

Preparation and physicochemical stability of 50 mg/mL hydroxychloroquine oral suspension in SyrSpendⓇ SF PH4 (dry).

In the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, hydroxychloroquine has been proposed as a potential agent to treat patients with COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 infection. Older adults are more susceptible to COVID-19 and some patients may require admission to the intensive care unit, where oral drug administration of solid forms may be compromised in many COVID-19 patients. However, a liquid formulation of hydroxychloroquine is not commercially available. This study describes how to prepare a 50 mg/mL hydroxychloroquine oral suspension using hydroxychloroquine sulfate powder and SyrSpendⓇ SF PH4 (dry) suspending vehicle. Moreover, a fully validated stability-indicating method has been developed to demonstrate the physicochemical stability of the compounded hydroxychloroquine oral suspension over 60 days under refrigeration (5 ± 3 °C). Finally, use of the proposed oral suspension provides a reliable solution to perform safe and accurate administration of hydroxychloroquine to patients with SARS-CoV-2 infection.

Concerns about pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) studies in the new therapeutic area of COVID-19 infection.

In the context of the COVID-19 pandemic, several drugs have been repurposed as potential candidates for the treatment of COVID-19 infection. While preliminary choices were essentially based on in vitro potency, clinical translation into effective therapies may be challenging due to unfavorable in vivo pharmacokinetic properties at the doses chosen for this new indication of COVID-19 infection. However, available pharmacokinetic and pharmacokinetic-pharmacodynamic studies suffer from severe limitations leading to unreliable conclusions, especially in term of dosing optimization. In this paper we propose to highlight these limitations and to identify some of the major requirements that need to be addressed in designing PK and PK-PD studies in this era of COVID. A special attention should be paid to pre-analytical and analytical requirements and to the proper collection of covariates affecting dose-exposure relationships (co-medications, use of specific organ support techniques and other clinical and para-clinical data). We also promote the development of population PK and PK-PD models specifically dedicated to COVID-19 patients since those previously developed for other diseases (SEL, malaria, HIV) and clinical situations (steady-state, non-ICU patients) are not representative of severe patients. Therefore, implementation of well-designed PK and PD studies targeted to COVID-19 patients is urgently needed. For that purpose we call for multi-institutional collaborative work and involvement of clinical pharmacologists in multidisciplinary research consortia.

Simultaneous determination of bisphenol A and its chlorinated derivatives in human plasma: Development, validation and application of a UHPLC-MS/MS method.

Bisphenol A (BPA) is a well-known ubiquitous chemical found in polycarbonate, polysulfone and epoxy resins, used in mass production for many consumer products. BPA exhibits endocrine disruptor properties that can potentially induce adverse health effects. In aquatic environments, it can react with chlorine to produce chlorinated derivatives (ClxBPAs). ClxBPAs exhibit oestrogenic activity 10 to 105 times higher than BPA itself. Assessing human exposure to endocrine disrupting chemicals is mandatory to assess health risk. Blood, as well as urine matrix, are commonly used to perform human biomonitoring. We therefore developed, fully validated and applied a method based on Ultra High Performance Liquid Chromatography couples to a Triple Quad Mass Spectrometer to determine BPA, monochlorobisphenol A (MCBPA), dichlorobisphenol A (DCBPA), trichlorobisphenol A (TCBPA) and tetrachlorobisphenol A (TTCBPA) in human blood plasma. The European Medicines Agency guidelines for bioanalytical method validation have been applied. Precision and trueness of the method were <15% at medium and high levels of quality control and <20% at the limits of quantification (LOQs). The LOQs were settled at 0.1 ng/mL for BPA, 0.02 ng/mL for TTCBPA and 0.005 ng/mL for MCBPA, DCBPA, and TCBPA. The analytical method was applied to ten patients suffering from end stage renal disease. BPA was quantified in all ten patients while MCBPA, DCBPA and TTCBPA were determined in three and TCBPA in four. In conclusion, we have successfully developed a highly sensitive method to determine BPA and ClxBPAs in human plasma. Thanks to this method, for the first time, we could demonstrate ClxBPAs occurrence in human blood.

Overcoming stability challenges during continuous intravenous administration of high-dose amoxicillin using portable elastomeric pumps.

While treatment of serious infectious diseases may require high-dose amoxicillin, continuous infusion may be limited by lack of knowledge regarding the chemical stability of the drug. Therefore, we have performed a comprehensive study so as to determine the chemical stability of high-dose amoxicillin solutions conducive to safe and effective continuous intravenous administration using portable elastomeric pumps. First, amoxicillin solubility in water was assessed within the range of 25 to 300 mg/mL. Then, amoxicillin solutions were prepared at different concentrations (25, 50, 125, 250 mg/mL) and stored in different conditions (5±2°C, 25±1°C, 30±1°C and 37±1°C) to investigate the influence of concentration and temperature on the chemical stability of amoxicillin. Finally, its stability was assessed under optimized conditions using a fully validated HPLC-UV stability-indicating method. Degradation products of amoxicillin were investigated by accurate mass determination using high-resolution mass spectrometry. Amoxicillin displayed limited water solubility requiring reconstitution at concentrations below or equal to 150 mg/mL. Amoxicillin degradation were time, temperature as well as concentration-dependent, resulting in short-term stability, in particular at high concentrations. Four degradation products of amoxicillin have been identified. Among them, amoxicilloic acid and diketopiperazine amoxicillin are at risk of allergic reaction and may accumulate in the patient. Optimized conditions allowing for continuous infusion of high-dose amoxicillin has been determined: amoxicillin should be reconstituted at 25 mg/mL and stored up to 12 hours at room temperature (22 ± 4°C) or up to 24 hours between 4 and 8°C.

Overexposure to Bisphenol A and Its Chlorinated Derivatives of Patients with End-Stage Renal Disease during Online Hemodiafiltration.

The health safety conditions governing the practice of online hemodiafiltration (OL-HDF) do not yet incorporate the risks related to the presence of endocrine disruptors such as bisphenol A (BPA). The aim of this study was to assess, for the first time, the exposure to BPA but also to its chlorinated derivatives (ClxBPA) (100 times more estrogenic than BPA) during OL-HDF. We demonstrated that BPA is transmitted by the different medical devices used in OL-HDF: ultrafilters, dialysis concentrate cartridges (and not only dialyzers, as previously described). Moreover, BPA has been found in dialysis water as well as in ultrapure dialysate and replacement fluid due to contamination of water coming from municipal network. Indeed, due to contaminations provided by both ultrafilters and water, high levels of BPA were determined in the infused replacement fluid (1033 ng.L-1) from the beginning of the session. Thus, our results demonstrate that dialysis water must be considered as an important exposure source to endocrine disruptors, especially since other micropollutants such as ClxBPA have also been detected in dialysis fluids. While assessment of the impact of this exposure remains to be done, these new findings should be taken into account to assess exposure risks in end-stage renal disease patients.

Bisphenol A, Chlorinated Derivatives of Bisphenol A and Occurrence of Myocardial Infarction in Patients with Type 2 Diabetes: Nested Case-Control Studies in Two European Cohorts.

A positive association between Bisphenol A (BPA) exposure and coronary heart disease has been shown, but not in patients with type 2 diabetes (T2D). During the treatment of drinking water, chlorination leads to the formation of chlorinated derivatives of Bisphenol A (ClxBPA), that have higher estrogenic activity than BPA. No evidence exists for a relationship between exposure to ClxBPA and myocardial infarction in patients with T2D. The objective of this study was to evaluate the relationship between exposure to BPA, ClxBPA and the occurrence of myocardial infarction (MI) in patients with T2D. Two nested case-control studies in two independent European cohorts were performed. Each case with incident MI during follow-up was matched to one control on age, sex, and personal cardiovascular history in the same cohort. Association between baseline urine concentrations of BPA and of ClxBPA and incident MI was determined. Exposure to BPA was 31% in the ESTHER cohort and 18% in the SURDIAGENE cohort. In a meta-analysis of the two studies, occurrence of MI was significantly associated with urine BPA detection: adjusted OR = 1.97 (1.05-3.70), p = 0.04. Exposure to ClxBPA significantly differed in the SURDIAGENE and ESTHER studies: 24% and 8%, respectively (p = 0.0003). It was very strongly associated with MI in the SURDIAGENE cohort with an adjusted odds ratio (OR) of 14.15 (2.77-72.40) but this association was not replicated in the ESTHER study: adjusted OR: 0.17 (0.02-1.23). Whether these results may be explained by different water chlorination processes in France and Germany, resulting in different ClxBPA exposure levels, requires further investigation.