70 research outputs found
Pharmacokinetic data for CYP3A4 probe substrates in healthy Humans.
No full text<p>This dataset contains all extracted informations used in the article "Inter-ethnic differences in CYP3A4 metabolism: A Bayesian meta-analysis for the refinement of uncertainty factors in chemical risk assessment" (<a href="https://doi.org/10.1016/j.comtox.2019.100092">https://doi.org/10.1016/j.comtox.2019.100092</a>).</p>FR; XLSX; [email protected]
Vers la nouvelle génération d'évaluation des risques des produits chimiques : métaanalyse Bayésienne de la variabilité humaine liée au métabolisme et aux transporteurs et application à la détermination des facteurs d'incertitude liés aux voies de cinétique
No full textIn the modern world, humans are exposed to a wide range of chemicals throughout their life. Human risk assessment of chemicals is of considerable public health importance and provides means to derive safe levels of acute and chronic exposure for subgroups of the human population including neonates, children, elderly and populations of different geographical ancestry and genetic polymorphisms. The application of pathway-related kinetic data to address human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default uncertainty factors. This thesis aims to 1) quantify human variability by means of Bayesian meta-analysis for a range of phase I, phase II metabolic pathways and transporters using pharmacokinetic markers of acute and chronic exposure or enzyme activity data from available probe substrate, 2) derive pathway-related variability distributions and pathway-related uncertainty factors for their future integration in physiologically based kinetic models for human risk assessment of chemicals.Dans le monde moderne, les humains sont exposés à une vaste gamme de produits chimiques tout au long de leur vie. L'évaluation des risques des substances chimiques pour l'homme revêt une importance capitale pour la santé publique et permet de calculer des niveaux sûrs d'exposition aiguë et chronique pour des sous-groupes de la population humaine, notamment les nouveau-nés, les enfants, les personnes âgées et les populations d’origine géographique et de polymorphismes génétiques différents. L'application des données cinétiques liées aux voies métaboliques pour tenir compte de la variabilité humaine dans la quantification du danger a le potentiel de réduire l'incertitude et de mieux caractériser la variabilité par rapport à l'utilisation traditionnelle des facteurs d'incertitude par défaut. Cette thèse vise à : 1) Quantifier la variabilité humaine au moyen d'une méta-analyse Bayésienne pour plusieurs voies métaboliques de phase I, phase II et transporteurs en utilisant des marqueurs pharmacocinétiques d'exposition aiguë et chronique ou des données d'activité enzymatique pour les substrats spécifiques disponible. 2) Estimer les distributions de variabilité liées aux voies métaboliques et les facteurs d’incertitudes liés à ces voies pour leur intégration future dans les modèles physiologiques basés sur la cinétique pour l'évaluation des risques des produits chimiques pour l'Homme
TKPlate: a web-based open source platform for Toxicokinetic and Toxicodynamic Modelling.
No full text<p>The TKPlate 1.0 application implements models for Toxicokinetic modelling (i.e. one compartment kinetic model and physiologically-based kinetic (PBK) models and toxicodynamic modelling (i.e. benchmark dose modelling) to integrate New approach methodologies (NAMs) in human health, animal health and environmental risk assessment (RA) of chemicals into a graphical interface. It is structured within a workflow of seven modules: 1) Input module to select the PBK models in humans, test species (rat, mice, rabbit, dog) and farm animals (pig, sheep, chicken and cattle), the chemical-specific data, exposure patterns and related time scales, 2) Forward dosimetry module to predict kinetic parameters and concentrations in blood plasma and organs of interests, 3) Reverse dosimetry module to back-calculate exposure from an internal dose profile using, for example, blood and urine biomonitoring data, 4) Toxicodynamic module for benchmark dose modelling on an internal dose basis using model averaging, 5) Dynamic energy budget module to assess the impact of chemicals on the life cycle of individuals and populations of species of ecological relevance, 6) MIXTOX module for deterministic risk characterisation of combined exposure to multiple chemicals in human health, animal health and ecological RA using the component-based approach and default assumption of dose addition allowing risk characterisation of multiple chemicals, 7) An automated report summarising inputs provided by the user and outputs, graphs and datasets. The technical development of TKplate 1.0 is described in an external scientific report associated with an EFSA editorial and two technical reports as a suer guide and case studies to illustrate applications of TKplate 1.0 (Bossier et al., 2020; Bossier et al., 2023a, b, c. Dorne et al., 2023). </p><p> </p><p>The material associated with this publication includes:</p><ul><li>The TKPlate 1.0 stand-alone application (tktd_1.0-22.tar.gz). The application can be installed in R using install.package.</li><li>Model codes implemented in MCSim: <ul><li>pbtk1cpt.model: 1-compartment kinetic model</li><li>generic_pbk.model as a generic PBK model for humans and test species (rat, mice, rabbit, dog)</li><li>farmanimalModel.model as generic PBK models for farm animals (cattle, pig, sheep, chicken)</li><li>cosmos_pbk.model as a human multi-route 6 compartment PBK model</li></ul></li></ul><p>These files contain the differential equations that are being solved. Input files from module 1 containing all input parameters are created dynamically within the application and depend on user input.</p><ul><li>QSAR.R as a model code for a QSAR model predicting partition coefficients for a given polar or neutral chemical in PBK model compartments (blood and organs) from input n-Octanol/Water partition coefficient.</li><li>The BMD R source code/ user manual and web application can be found in the following zenodo publication: <a href="https://zenodo.org/record/3760370">https://zenodo.org/record/3760370</a> (Varewyck et al., 2017) and <a href="https://r4eu.efsa.europa.eu/app/bmd">https://r4eu.efsa.europa.eu/app/bmd</a> respectively. In TKplate the R source code has been slightly modified in TKPlate to allow BMD modelling based on internal dose instead of external dose. In addition, the user can also access the new Bayesian BMD application is described under <a href="https://zenodo.org/record/7986184">https://zenodo.org/record/7986184</a> (Kremer et al., 2022) and is accessible under : https://r4eu.efsa.europa.eu/app/bmdbayesian</li><li>R package for the Dynamic Energy Budget model</li><li>Several Excel and csv files used throughout the application have also been uploaded:<ul><li>speciesData.xlsx with physiological parameters used to build the generic PBK models for humans, laboratory animals (rat, mice, rabbit, dog) and farm animals (pig, sheep, chicken and cattle) </li><li>data_chem.csv and data_TK.csv as templates to upload chemical-specific parameters and TK data respectively</li><li>PopGen.csv as a pre-made population used in the human generic PBK model (McNally et al., 2014). PopGen contains relevant physiological information and represent 1000 individuals, 500 per sex from a Caucasian population. BMI range from 21 to 24 and height is in between 150 and 190 for women and 160 and 200 for men. Since PopGen outputs are derived from non-truncated distributions, variability in parameter value is limited to the 95th percentile for each parameter to avoid the creating of unrealistic individuals.</li><li>Variability distributions in human metabolism from previously published meta-analysis. These include Phase I enzymes (CYP3A4, CYP2D6, CYP2C9, carboxyl-esterases) and Phase II enyzmes (UGTs).</li></ul></li></ul><p>EU; R; MCSim; [email protected] </p>
Avis de l'Anses relatif à la mise en œuvre d'un plan de contrôle orienté sur les denrées alimentaires d'origine animale et végétale produites sur le pourtour du golfe de Fos-sur-Mer
No full textLe pourtour du Golfe de Fos-sur-Mer est caractérisé par une forte densité de population, mais aussi par la présence d’une vaste zone industrialo-portuaire (ZIP) dont l’activité entraine le rejet de nombreuses substances dans l’atmosphère et les milieux aquatiques. Dans ce contexte, afin de déterminer l’exposition alimentaire des résidents de cette zone à ces contaminants industriels, l’Association de Défense et Protection du Littoral du Golfe de Fos (ADPLGF) a concentré ses recherches sur certaines substances (métaux lourds, HAP, dioxines et PCB) dans différentes denrées alimentaires produites localement, sur des échantillons prélevés entre 2009 et 2015 . Selon cette association, les denrées alimentaires d’origine animale produites à proximité de la ZIP du Golfe de Fos-sur-Mer sont contaminées par des polluants chimiques et d’après les auteurs, l’activité industrielle serait la cause de ces observations. Le rapport de l’ADPLGF a été présenté en 2017 à l’Agence régionale de santé (ARS) Provence-Alpes-Côte d’Azur (PACA) avant publication en février 2018 dans la presse.Dans le cadre des plans de surveillance et plans de contrôle (PSPC) et notamment d’un plan de surveillance renforcé dans la zone du Golfe de Fos-sur-Mer sur les matrices animales, la Direction départementale de la protection des populations (DDPP) des Bouches-du-Rhône a effectué, en 2018, 40 prélèvements destinés à la recherche de métaux lourds, dioxines, PCBDL et PCB-NDL répartis sur les matrices suivantes : viandes ovine et bovine, miel, poissons d’élevage et sauvages, mollusques bivalves et crustacés. Tous les résultats d’analyses obtenus se sont révélés conformes aux teneurs maximales fixées dans les denrées alimentaires par le Règlement (CE) N°1881/20062 et par les règlements le modifiant.Dans ce contexte, l’Anses a été saisie le 19 avril 2018 par la DGAL, la DGS et la DGPR d’une demande de méthodologie destinée à mettre en place un plan de contrôle orienté sur les denrées alimentaires d’origine animale et végétale produites et collectées (concernant les produits de la mer) sur le pourtour du Golfe de Fos-sur-Mer (prélèvements à la production et à la collecte). Le protocole proposé reposera sur un effort d’échantillonnage plus important que celui mené dans le cadre des plans de surveillance afin d’analyser plus finement le territoire
Updated consumer risk assessment of fluoride in food and drinking water including the contribution from other sources of oral exposure
No full text: This updated risk assessment evaluated evidence on potential adverse health effects of fluoride related to all sources of oral exposure as mandated by the European Commission. Fluoride benefit assessment was not included. Effects on the central nervous system, thyroid and bone were prioritised. Evidence from human studies indicates that total fluoride intake is associated with adverse effects on the developing brain at drinking water concentrations > 1.5 mg/L. The evidence of such associations below 1.5 mg/L was not sufficiently consistent to draw conclusions for risk assessment. Using drinking water concentration of 1.5 mg/L as a reference point, a safe level of intake including all sources of oral exposure of 3.3 mg/day was established for pregnant women to protect the fetus. This safe level of intake was extended to apply to other adults and children > 8 years. It is considered protective also against possible adverse effects on thyroid function and bone mineralisation, for which associations have been observed at water concentrations > 1.5 mg/L. Dental fluorosis was considered the most sensitive endpoint for children ≤ 8 years. Tolerable upper intake levels (UL) of 1.0, 1.6 and 2.0 mg/day were established for infants, toddlers and children 4-8 years, respectively. These ULs are considered protective against other possible adverse effects of fluoride, including neurodevelopmental outcomes. Aggregate exposure included intake of fluoride from food, drinking water, discretionary salt and (ingested) dental care products. Aggregate exposure based on the mean concentration of fluoride in EU drinking water (submitted data) was below the above health-based guidance values (HBGVs) for all age groups. Aggregate exposure exceeds the HBGVs at the 95th percentile of intake in the scenario of the P95 concentration of fluoride in EU drinking water, for all age groups except adolescents. The risk assessment suggests that the current legal limit for drinking water (1.5 mg/L) in the EU is not sufficiently protective
Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs
No full textInternational audienceThe major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone. Because of the polymorphic nature of CYP2D6, considerable inter-phenotypic and inter-ethnic differences in the pharmaco/toxicokinetics (PK/TK) and metabolism of CYP2D6 substrates exist with potential consequences on the pharmacology and toxicity of chemicals. Here, large extensive literature searches have been performed to collect PK data from published human studies for a wide range of pharmaceutical probe substrates and investigate human variability in CYP2D6 metabolism. The computed kinetic parameters resulted in the largest open source database, quantifying inter-phenotypic differences for the kinetics of CYP2D6 probe substrates in Caucasian and Asian populations, to date. The database is available in supplementary material (CYPD6 DB) and EFSA knowledge junction (DOI to added). Subsequently, meta-analyses using a hierarchical Bayesian model for markers of chronic oral exposure (oral clearance, area under the plasma concentration time curve) and acute oral exposure (maximum plasma concentration (Cmax) provided estimates of inter-phenotypic differences and CYP2D6-related uncertainty factors (UFs) for chemical risk assessment in Caucasian and Asian populations classified as ultra-rapid (UM), extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). The model allowed the integration of inter-individual (i.e. inter-phenotypic and inter-ethnic), inter-compound and inter-study variability together with uncertainty in each PK parameter. Key findings include 1. Higher frequencies of PMs in Caucasian populations compared to Asian populations (>8% vs 1-2%) for which EM and IM were the most frequent phenotype. 2. Large inter-phenotypic differences in PK parameters for Caucasian EMs (coefficients of variation (CV) > 50%) compared with Caucasian PMs and Asian EMs and IMs (i.e CV < 40%). 3. Inter-phenotypic PK differences between EMs and PMs in Caucasian populations increase with the quantitative contribution of CYP2D6 for the metabolism (fm) for a range of substrates (fm CYP2D6 range: 20-95% of dose) (range: 1-54) to a much larger extent than those for Asian populations (range: 1-4). 4. Exponential meta-regressions between Fm CYP2D6 in EMs and inter-phenotypic differences were also shown to differ between Caucasian and Asian populations as well as CYP2D6-related UFs. Finally, implications of these results for the risk assessment of food chemicals and emerging designer drugs of public health concern, as CYP2D6 substrates, are highlighted and include the integration of in vitro metabolism data and CYP2D6 variability distributions for the development of quantitative in vitro in vivo extrapolation models
The Effectiveness and Cost-Effectiveness of a Rural Employer-Based Wellness Program
No full textContext: The cost-effectiveness of employer-based wellness programs has been previously investigated with favorable financial and nonfinancial outcomes being detected. However, these investigations have mainly focused on large employers in urban settings. Very few studies examined wellness programs offered in rural settings.Purpose: This paper aims to explore the effectiveness and cost-effectiveness of a rural employer-based wellness program.Methods: Six rural employers were categorized into 3 groups: a control group and 2 intervention groups with varying degrees of wellness activities. Participants were asked to complete an annual health risk assessment (HRA) that addressed 16 wellness areas. At the conclusion of 4 years, HRA and effectiveness data were utilized to examine program effectiveness and combined with program costs to estimate cost-effectiveness.Findings: The Coaching and Referral group-the highest in intensity of participant engagement-exhibited superior improvement in several wellness areas and in percentage of employees with good health indicators compared to the control and the Trail Marker, lower-intensity intervention groups. However, the Trail Markers had more favorable cost-effectiveness ratios.Conclusions: Rural worksite wellness programs have shown great potential in their effectiveness and cost-effectiveness. Such programs need not be too aggressive, tedious, and costly to generate a favorable return for employers and funders. However, employers should be encouraged to experiment with different levels of wellness program intensities until a more favorable outcome can be realized. © 2010 National Rural Health Association.Anderson DR, 2000, AM J HEALTH PROMOT, V15, P45; Arcury TA, 2005, J RURAL HEALTH, V21, P337, DOI 10.1111-j.1748-0361.2005.tb00104.x; Aronson RE, 2004, J RURAL HEALTH, V20, P76, DOI 10.1111-j.1748-0361.2004.tb00010.x; BOWCUTT M, 2004, NURSE LEADER, V2, P25, DOI 10.1016-j.mnl.2004.01.015; Edington DW, 2008, INT J WORKPLACE HLTH, V1, P8, DOI 10.1108-17538350810865569; Faghri PD, 2008, J OCCUP ENVIRON MED, V50, P1378, DOI 10.1097-JOM.0b013e3181862471; GOLASZEWSKI T, 1992, J OCCUP ENVIRON MED, V34, P1164; Hennessy CH, 2001, J RURAL HEALTH, V17, P364, DOI 10.1111-j.1748-0361.2001.tb00290.x; Kelsey KS, 2006, AM J HEALTH BEHAV, V30, P199; Liu JH, 2008, J RURAL HEALTH, V24, P407, DOI 10.1111-j.1748-0361.2008.00188.x; Mills PR, 2007, AM J HEALTH PROMOT, V22, P45; Pelletier KR, 2005, J OCCUP ENVIRON MED, V47, P1051, DOI 10.1097-01.jom.0000174303.85442.bf; PERRIN KM, 2008, J MANAGE MARKETING H, V1, P382; Rice Muriel C, 2005, AWHONN Lifelines, V9, P468, DOI 10.1177-1091592305285273; Schult TMK, 2006, J OCCUP ENVIRON MED, V48, P541, DOI 10.1097-01.jom.0000222565.68934.0b; Tilson EC, 2002, J RURAL HEALTH, V18, P547; Walton C, 1999, AAOHN J, V47, P449; *WELLS, 2009, WELLN ASS10
Effect of high-frequency radiations on survival of the honeybee (Apis mellifera L.)
No full textInternational audienceRecent studies succeeded in developing a method to automatically record honeybees going in and out of the hive. Honeybees were individualized with radio frequency identification (RFID) tags glued onto their dorsal surface and detected at the hive entrance by readers emitting high-frequency (HF) radio waves. In this work we search for a possible adverse effect of HF on honeybees' survival. Eight-day-old honeybees were exposed to HF (13.56 MHz) or ultra-high-frequency (UHF, 868 MHz) radio waves for 2 h split into ON and OFF periods. The ON/OFF ratio was 1:3 (OFF duration 3, 90, 180, 370 and 360 s) or 1:5 (OFF duration 300 s). Dead individuals were counted every day, and the cumulative mortality rates of exposed and non-exposed honeybees were compared 7 days after exposure. Out of the five experimental conditions, we observed an increase in mortality in two conditions, once after HF and once after UHF exposure, with OFF duration of 5 min or more. We then recommend limiting exposure of honeybees to radio waves to less than 2 h per day, and we conclude that the RFID parameters, like those we used in the field for monitoring hive activity, present no adverse effects for honeybees
Avis de l'Anses relatif à la mise en œuvre d'un plan de contrôle orienté sur les denrées alimentaires d'origine animale et végétale produites sur le pourtour du golfe de Fos-sur-Mer
No full textLe pourtour du Golfe de Fos-sur-Mer est caractérisé par une forte densité de population, mais aussi par la présence d’une vaste zone industrialo-portuaire (ZIP) dont l’activité entraine le rejet de nombreuses substances dans l’atmosphère et les milieux aquatiques. Dans ce contexte, afin de déterminer l’exposition alimentaire des résidents de cette zone à ces contaminants industriels, l’Association de Défense et Protection du Littoral du Golfe de Fos (ADPLGF) a concentré ses recherches sur certaines substances (métaux lourds, HAP, dioxines et PCB) dans différentes denrées alimentaires produites localement, sur des échantillons prélevés entre 2009 et 2015 . Selon cette association, les denrées alimentaires d’origine animale produites à proximité de la ZIP du Golfe de Fos-sur-Mer sont contaminées par des polluants chimiques et d’après les auteurs, l’activité industrielle serait la cause de ces observations. Le rapport de l’ADPLGF a été présenté en 2017 à l’Agence régionale de santé (ARS) Provence-Alpes-Côte d’Azur (PACA) avant publication en février 2018 dans la presse.Dans le cadre des plans de surveillance et plans de contrôle (PSPC) et notamment d’un plan de surveillance renforcé dans la zone du Golfe de Fos-sur-Mer sur les matrices animales, la Direction départementale de la protection des populations (DDPP) des Bouches-du-Rhône a effectué, en 2018, 40 prélèvements destinés à la recherche de métaux lourds, dioxines, PCBDL et PCB-NDL répartis sur les matrices suivantes : viandes ovine et bovine, miel, poissons d’élevage et sauvages, mollusques bivalves et crustacés. Tous les résultats d’analyses obtenus se sont révélés conformes aux teneurs maximales fixées dans les denrées alimentaires par le Règlement (CE) N°1881/20062 et par les règlements le modifiant.Dans ce contexte, l’Anses a été saisie le 19 avril 2018 par la DGAL, la DGS et la DGPR d’une demande de méthodologie destinée à mettre en place un plan de contrôle orienté sur les denrées alimentaires d’origine animale et végétale produites et collectées (concernant les produits de la mer) sur le pourtour du Golfe de Fos-sur-Mer (prélèvements à la production et à la collecte). Le protocole proposé reposera sur un effort d’échantillonnage plus important que celui mené dans le cadre des plans de surveillance afin d’analyser plus finement le territoire
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