Toxicokinetics in environmental health : application to the assessment of exposure to endocrine disruptors

Le bisphénol A (BPA), ubiquitaire dans l'environnement, est reconnu comme étant un perturbateur endocrinien (PE). La forte réactivité du BPA avec le chlore entraine la formation de dérivés chlorés du BPA (ClxBPA), possédant une activité perturbatrice endocrinienne supérieure au BPA. En santé environnementale, l'évaluation du risque chez l'homme implique notamment la mise en place d'études de biomonitoring et de toxicocinétique nécessitant l'analyse des micropolluants environnementaux dans les milieux biologiques.Afin d'estimer l'exposition des populations au BPA et ClxBPA, une méthode d'analyse par LC-MS/MS du BPA et des ClxBPA non conjugués a été validée dans l'urine. Cette méthode a ensuite été modifiée afin d'améliorer la rapidité et la sensibilité du dosage, et a été appliquée à la mesure de l'exposition aux PE dans une cohorte de femmes enceintes.L'étude de la toxicocinétique du BPA montre la formation de dérivés conjugués, éliminés par voie urinaire. Classiquement, pour la mesure des dérivés conjugués, des méthodes indirectes utilisant la déconjugaison enzymatique sont proposées. Dans ce cadre, nous avons développé une méthode originale permettant de valider l'efficacité de la déconjugaison. Si la mesure indirecte des métabolites après déconjugaison semble plus aisée, il reste néanmoins plus rationnel de doser directement l'analyte recherché. C'est pourquoi, après synthèse des substances étalons, nous avons pu développer, pour la 1ère fois, une méthode de dosage des dérivés glucuronides et sulfates du BPA et du Cl2BPA dans l'urine.Ce travail propose, à travers notamment le développement de méthodes d'analyse, des outils fiables pour la mesure de l'exposition aux PE.Bisphenol A (BPA), a well-known endocrine disruptor (ED), is ubiquitously found in the environment. The high reactivity of BPA with chlorine results in the formation of chlorinated derivatives of BPA (ClxBPA), having a higher endocrine disrupting activity than BPA. In the field of environmental health sciences, human risk assessment implies, in particular, to perform biomonitoring and toxicokinetic studies requiring the analysis of environmental micropollutants in biological matrices. To estimate population exposure to BPA and ClxBPA, a LC-MS/MS method to assay BPA and ClxBPA was validated in urine. This method was then modified to improve the speed and sensitivity of the assay, and was applied to the measurement of ED exposure in a cohort of pregnant women.Toxicokinetic studies of BPA report the formation of conjugates, excreted in urine. Conventionally, for the measurement of conjugated derivatives, indirect methods using enzymatic deconjugation are proposed. In this context, we have developed an original method for validating the deconjugation efficiency.If the indirect measurement of metabolites after deconjugation appears easier, it is more rationale to assay directly the metabolite. Therefore, after synthesis of analytical standards, we were able to develop, for the first time, a method for assaying glucuronides and sulfates BPA and Cl2BPA derivatives in urine.This work offers, especially through the development of analytical methods, reliable tools for assessing human exposure to ED

Modélisation pharmacocinétique-pharmacodynamique de l'activité in vitro de la ciprofloxacine sur pseudomonas aeruginosa

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Semimechanistic Pharmacokinetic-Pharmacodynamic Model with Adaptation Development for Time-Kill Experiments of Ciprofloxacin against Pseudomonas aeruginosa▿

The objective of this study was to implement a semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of ciprofloxacin against Pseudomonas aeruginosa in vitro. Time-kill curves were generated with an initial inoculum close to 5 × 106CFU/ml of P. aeruginosa PAO1 and constant ciprofloxacin concentrations between 0.12 and 4.0 μg/ml (corresponding to 0.5× and 16× MIC). To support the model, phenotypic experiments were conducted with the PAO7H mutant strain, which overexpresses the MexEF OprN efflux pump and phenyl arginine β-naphthylamide (PAβN), a known efflux inhibitor of main Mex multidrug efflux systems. A population approach was used for parameter estimation. At subinhibitory ciprofloxacin concentrations (0.12 and 0.25 μg/ml), an initial CFU decay followed by regrowth was observed, attesting to rapid emergence of bacteria with increased but moderate resistance (8-fold increase of MIC). This phenomenon was mainly due to an overexpression of the Mex protein efflux pumps, as shown by a 16-fold diminution of the MIC in the presence of PAβN in these strains with low-level resistance. A PK-PD model with adaptation development was successfully used to describe these data. However, additional experiments are required to validate the robustness of this model after longer exposure periods and multiple dosing regimens, as well as in vivo

Estimating drinking-water ingestion and dermal contact with water in a French population of pregnant women: the EDDS cohort study

International audienceIn assessment of water pollutant risk, water-use habits of pregnant women have been estimated by questionnaires or diaries, in Italy, Spain, USA and Great Britain. (1-10) Some studies have [...]The aim of the present study, a part of the Endocrine Disruptor Deux-Sevres (EDDS) cohort study, was to estimate water- use habits of pregnant French women. The study population consisted of 132 pregnant women living in Deux-Sevres (France) in 2012- 2013, in areas where drinking water is exclusively produced by surface water. Drinking-water data included ingested water (tap, bottled and filtered) and ingestion place (home, work and elsewhere). Dermal contact with water included showering, bathing, swimming, spa use, hand-washing and other water activities. Data were collected through face-to-face interviews at second and third trimesters of pregnancy with a 1-day-recall questionnaire. Intertrimestral differences in water-use habits were assessed. Predictors of water ingestion and duration of dermal contact with water were assessed with multiple linear regressions. At the second trimester of pregnancy, the mean total drinking-water ingestion was 1.8 [+ or -] 0.6 l per day (mean and SD), 71% of which was tap water. Total drinking-water ingestion was not different between both trimesters but ingestion place differed. Dermal contact with water estimate was 188 [+ or -] 118 and 173[+ or -] 92min/week at second and third trimesters, respectively. Smoking increased water ingestion 777 ml/day 95% CI (171-1384). Duration of dermal contact in spring was 30 min/week 95% CI (13-48) higher than in winter. Obese women spend 26 min/week 95% CI (2-50) more showering than women with recommended weight. Our estimates of pregnant French women's exposure to water will help researchers to better assess water pollutant risks. Journal of Exposure Science and Environmental Epidemiology (2015) 25, 308-316; doi:10.1038/jes.2014.48;published online 30 July 2014 Keywords: water contaminants; drinking-water ingestion; dermal contact with water; pregnancy; Franc

Ultrasensitive determination of bisphenol A and its chlorinated derivatives in urine using a high-throughput UPLC-MS/MS method

International audienceBisphenol A (BPA) is a well-known endocrine disruptor. Chlorinated derivatives of BPA (ClxBPA) may be formed by reaction of chlorine with BPA present in drinking water. ClxBPA exhibit a higher level of estrogenic activity than BPA. While many studies have reported detectable BPA concentrations in urine, only very few studies were conducted in regards to ClxBPA. Since ClxBPA are potentially more toxic, it is important to assess large-scale exposure of the general population. Indeed, in the field of environment health, large studies are required to assess exposure to pollutants at ultratrace concentrations; therefore, analytical methods have to be rapid and sensitive. This work intends to validate a highly sensitive and rapid analytical method suitable to evaluate BPA and ClxBPA exposures during large-scale biomonitoring studies. For that purpose, a method based on online solid-phase extraction coupled with isotope dilution ultrahigh - performance liquid chromatography-tandem mass spectrometry was developed and validated according to accepted guidelines. The matrix-matched calibration curve ranged from 0.25 to 16.0 ng mL¹ and from 0.025 to 1.60 ng mL¹ for BPA and ClxBPA, respectively. This method was precise (the intra- and inter-day coefficients of variation of quality control were <16.4 %) and accurate (bias ranged from 4.0 to 16.8 %). The limit of quantification was validated at 0.25 and 0.025 ng mL¹, for BPA and ClxBPA, respectively. The limit of detection was estimated for each experiment performed. Finally, this method is rapid and sensitive enough to be carried out during biomonitoring studies of BPA and ClxBPA in human urine

Exposition hydrique au bisphénol A et à ses dérivés chlorés et liens avec le cancer du sein : étude de faisabilité BREDI I (Breast and Endocrine Disrupter Investigation Part 1)

Il existe une relation entre exposition aux perturbateurs endocriniens (PE) et carcinogenèse animale. Cependant, les données épidémiologiques sont insuffisantes. Le bisphénol A (BPA) est un PE ubiquitaire présent dans l’eau potable. Ses dérivés chlorés (Clx-BPA) sont suspectés d’avoir une action PE 100 fois supérieure. L’objectif de ce travail était d’évaluer la faisabilité d’une étude d’exposition hydrique au BPA et aux Clx-BPA dans une population de patientes opérées du sein. L’étude a été menée au CHU de Poitiers auprès de trois populations de femmes opérées du sein classées selon la gravité de leur lésion. Trois façons d’évaluer l’exposition hydrique ont été explorées : dosage dans des matrices biologiques, dans l’eau du robinet et administration d’un questionnaire sociodémographique validé. Le critère de jugement principal était la concentration en composés dans l’eau ou les matrices biologiques et les quantités d’eau apportées par voie orale et cutanée selon le questionnaire. Dans l’eau de boisson analysée, le BPA a été quantifié chez la totalité des patientes (116 ± 162 ng∙L‑1). Les concentrations en Clx-BPA étaient de 1,85 ± 0,70 ng∙L‑1. Les concentrations urinaires en BPA étaient de 2,6 ng∙mL‑1 en préopératoire et 3,8 ± 5,5 ng∙mL‑1 en postopératoire, les Clx-BPA n’ayant pas été quantifiés. Dans le tissu adipeux mammaire, le BPA a été retrouvé à 1,265 ± 0,058 ng∙g‑1, le BPA et le Clx-BPA n’ayant été détectés qu’à deux reprises. Cette étude a montré la faisabilité des dosages du BPA et des Clx-BPA dans les matrices biologiques et l’eau du robinet. La mise en place d’une cohorte multicentrique permettra d’étudier la relation entre exposition à ces PE et cancer du sein.There is a relationship between exposure to endocrine disrupting chemicals (EDCs) and animal carcinogenesis. However, epidemiological data are insufficient. Bisphenol A (BPA) is a ubiquitous EDC present in drinking water. Its chlorinated derivatives (Clx-BPA) are suspected to have an ED action 100 times stronger than BPA itself. The aim of this study was to assess the feasibility of a trial about water exposure to BPA and Clx-BPA in a population of patients having breast surgery. The study was conducted at the University Hospital of Poitiers in three populations of women having breast surgery and classified according to the severity of their injury. Three methods to assess water exposure were explored: determination in biological matrices, in tap water and administration of a validated socio-demographic questionnaire for water exposure. The primary endpoint was the concentration of compounds in water or biological matrices and the amount of water provided by oral and dermal routes according to the questionnaire. In drinking water samples, BPA was quantified for every patient (116 ± 162 ng∙L‑1). Clx-BPA concentrations were 1.85 ±  0.70 g∙L‑1. Urinary BPA concentrations were 2.6 ng∙mL‑1 preoperatively and 3.8 ± 5.5 ng∙mL‑1 postoperatively; CLx-BPA have not been quantified. In breast adipose tissue, BPA was found at 1.265 ± 0.058 ng∙g‑1, whereas BPA and BPA-Clx were only found two times. This study demonstrated the feasibility of BPA and Clx-BPA determinations in biological matrices and tap water. Performing a multicenter cohort study would allow an investigation of the relationship between exposure to EDCs and breast cancer

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

International audienceWhile 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

Determination of bisphenol A in water and the medical devices used in hemodialysis treatment

International audienc