Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Increasingly, health risk assessment is addressing multiple pathway exposures to multiple contaminants. We reviewed aggregated exposure and cumulative risk approaches for contemporary and ubiquitous semivolatile organic compounds (SVOC). We identified 22 studies aggregating exposure pathways, and 31 cumulating risk. Exposure aggregation is based on the addition of pathway-specific doses, using kinetic modeling where it exists, and classic external dose equations otherwise. In most cases, exposure is dominated by a single route or source of exposure - mainly the oral pathway - via dietary or non-dietary exposure. Preferential routes and sources of exposure are influenced by SVOC physical-chemical properties such as vapor pressure. The cumulative risk approach for contaminants is based on dose addition. Simple sum of hazard quotient (Hazard Index: HI) is the most commonly used cumulative risk assessment approach, while Relative Potency Factor (RPF) appeared to the best suited – although this calls for a level of toxicological information that limits the number of compounds that can be studied simultaneously. Where both were performed, moving from HI to more refined approach produced similar results. In conclusion, both approaches - exposure aggregation and cumulative risk - rely on simple assumptions. Nevertheless, they allow uncertainty to be reduced, in comparison with source-by-source or chemical-by-chemical approaches.
ISSN: 0013-9351

hal-01635759
https://hal.archives-ouvertes.fr/hal-01635759
https://hal.archives-ouvertes.fr/hal-01635759/document
https://hal.archives-ouvertes.fr/hal-01635759/file/Pelletier%202017%20Review%20%20rev2.pdf
DOI : 10.1016/j.envres.2017.06.022

Éditeur(s) : Elsevier
Résumé : The uptake and loss kinetics of Cd were determined in two species of scallops from the European coasts, the variegated scallop Chlamys varia and the king scallop Pecten maximus, following exposures via seawater, phytoplankton and sediment using highly sensitive radiotracer techniques (Cd-109). Results indicate that, for seawater and dietary pathways, C. varia displays higher bioaccumulation capacities in terms of uptake rate from water and fraction absorbed from ingested food (assimilation efficiency) than Pecten maximus. Regarding sediment exposure, P. maximus displayed low steady-state Cd transfer factor (TFSS < 1); however, once incorporated, a very large part of Cd transferred from sediment (92%) was strongly retained within R maximus tissues. Both species showed a high retention capacity for Cd (biological half-life, T-b1/2 > 4 months), suggesting efficient mechanisms of detoxification and storage in both species. The digestive gland was found to be the main storage organ of Cd in the two scallops regardless of the exposure pathway. However, Cd was stored differently within this organ according to the species considered: 40% of the total Cd was found in the soluble cellular fraction in C. varia whereas this soluble fraction reached 80% for P. maximus. This suggests that the two species displayed different Cd detoxification/storage mechanisms. Finally, the present study has determined the relative contribution of the different exposure pathways to global Cd bioaccumulation for the two scallop species. Results clearly show that for both species, food constitutes the major accumulation pathway, contributing for >99% and 84% of the global Cd bioaccumulation in C. varia and R maximus, respectively. This work confirms the previous assumption, derived from a bibliographic overview, that dietary pathway plays a prevalent role in metal bioaccumulation in Pectinidae. (C) 2007 Elsevier B.V. All rights reserved.
Journal of Experimental Marine Biology and Ecology (0022-0981) (Elsevier), 2007-12 , Vol. 353 , N. 1 , P. 58-67

Droits : 2007 Elsevier B.V. All rights reserved.
http://archimer.ifremer.fr/doc/2007/publication-3581.pdf
DOI:10.1016/j.jembe.2007.09.001
http://archimer.ifremer.fr/doc/00000/3581/

Éditeur(s) : HAL CCSD
Résumé : International audience
Increasingly, health risk assessment is addressing multiple pathway exposures to multiple contaminants. We reviewed aggregated exposure and cumulative risk approaches for contemporary and ubiquitous semivolatile organic compounds (SVOC). We identified 22 studies aggregating exposure pathways, and 31 cumulating risk. Exposure aggregation is based on the addition of pathway-specific doses, using kinetic modeling where it exists, and classic external dose equations otherwise. In most cases, exposure is dominated by a single route or source of exposure - mainly the oral pathway - via dietary or non-dietary exposure. Preferential routes and sources of exposure are influenced by SVOC physical-chemical properties such as vapor pressure. The cumulative risk approach for contaminants is based on dose addition. Simple sum of hazard quotient (Hazard Index: HI) is the most commonly used cumulative risk assessment approach, while Relative Potency Factor (RPF) appeared to the best suited - although this calls for a level of toxicological information that limits the number of compounds that can be studied simultaneously. Where both were performed, moving from HI to more refined approach produced similar results. In conclusion, both approaches - exposure aggregation and cumulative risk - rely on simple assumptions. Nevertheless, they allow uncertainty to be reduced, in comparison with source-by-source or chemical-by-chemical approaches.
Environmental Research

hal-01579608
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579608
DOI : 10.1016/j.envres.2017.06.022
PUBMED : 28732321

Éditeur(s) : HAL CCSD
Résumé : International audience
Multiple chemicals are emitted in residential accommodation. Aggregate Daily Doses (ADD) (ng/kg-bw/d) were estimated for 32 semivolatile organic compounds (SVOCs) of different chemical families that are frequently detected in French dwellings in both air and settled dust. Daily doses were determined using steady-state models for the population, categorized into 11 age groups covering birth to age 30. Three routes of exposure were taken into account: dust ingestion, inhalation (gaseous and particulate phases) and dermal contact with the gaseous phase of air. Contamination levels were preferentially retrieved from large, nationwide representative datasets. A two-dimensional probabilistic approach was used to assess parametric uncertainty and identify the most influential factors. For children aged 2 to 3 years, ADD estimates spanned orders of magnitude, with median values ranging from 8.7 pg/kg-bw/d for 2,2′,3,4,4′-pentabromodiphenylether (BDE 85) to 1.3 μg/kg-bw/d for di-isobutyl phthalate (DiBP). Inhalation, ingestion and dermal pathway contributed at varying levels, and depending on compound, air was the dominant medium for 28 of the 32 compounds (either by inhalation or dermal contact). Indoor exposure estimate variance was mainly driven by indoor contamination variability, and secondarily by uncertainty in physical and chemical parameters. These findings lend support to the call for cumulative risk assessment of indoor SVOCs. © 2017 Elsevier Ltd
ISSN: 01604120

hal-01616433
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616433
DOI : 10.1016/j.envint.2017.08.024
PUBMED : 28950160

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Perinatal exposure to endocrine-disrupting chemicals may affect thyroid hormones homeostasis and impair brain development. Chlordecone, an organochlorine insecticide widely used in the French West Indies has known estrogenic and progestin properties, but no data is available, human or animal, on its action on thyroid hormone system. Our aim was to evaluate the impact of perinatal exposure to chlordecone on the thyroid hormone system of a sample of infants from the Timoun mother-child cohort in Guadeloupe and their further neurodevelopment. Chlordecone was measured in cord blood and breast milk samples. Thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3), free thyroxine (FT4) were determined in child blood at 3 months (n=111). Toddlers were further assessed at 18 months using an adapted version of the Ages and Stages Questionnaire (ASQ). Cord chlordecone was associated with an increase in TSH in boys, whereas postnatal exposure was associated with a decrease in FT3 overall, and in FT4 among girls. Higher TSH level at 3 months was positively associated with the ASQ score of fine motor development at 18 months among boys, but TSH did not modify the association between prenatal chlordecone exposure and poorer ASQ fine motor score. Perinatal exposure to chlordecone may affect TSH and thyroid hormone levels at 3 months, differently according to the sex of the infant. This disruption however did not appear to intervene in the pathway between prenatal chlordecone exposure and fine motor child development.
ISSN: 0013-9351

hal-01134317
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134317
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134317/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134317/file/Perinatal%20exposure%20to%20chlordecone_accepted.pdf
PUBMED : 25747818

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Herbicides are generally the most extensively used of the pesticides applied to agricultural crops. However, the literature contains little evidence useful in assessing the potential sources of the general population's exposure to herbicides, including by residential proximity to crops. The objective of this study was to take advantage of data from the PELAGIE mother-child cohort to identify the main determinants of the body burden of exposure to the chloroacetanilide and triazine herbicides commonly used on corn crops in Brittany, France, before 2006. Urine samples from a randomly selected subcohort of women in the first trimester of pregnancy (n=579) were assayed for herbicide metabolites. The residential exposure resulting from proximity to corn crops was assessed with satellite-image-based scores combined with meteorological data. Data on diet, drinking tap water (from the public water supply), occupations, and household herbicide use were collected by questionnaires. Herbicides were quantified in 5.3% to 39.7% of urine samples. Alachlor and acetochlor were found most frequently in the urine of women living in rural areas. The presence of dealkylated triazine metabolites in urine samples was positively associated with residential proximity to corn crops (OR=1.38, 95% CI: 1.05-1.80). Urinary metabolites of both atrazine and dealkylated triazine were correlated with tap water consumption (OR=2.94, 1.09-7.90, and OR=1.82, 1.10-3.03, respectively); hydroxylated triazine metabolites were correlated with fish intake (OR=1.48, 1.09-1.99). This study reinforces previous results that suggest that environmental contamination resulting from agricultural activities may contribute to the general population's exposure to herbicides.
Environment International

hal-00966842
https://hal.archives-ouvertes.fr/hal-00966842
https://hal.archives-ouvertes.fr/hal-00966842/document
DOI : 10.1016/j.envint.2013.10.010
PUBMED : 24246238

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Few studies have explored how noise might contribute to social health inequalities, and even fewer have considered infant mortality or its risk factors as the health event of interest.In this paper, we investigate the impact of neighbourhood characteristics - both socio-economic status and ambient noise levels - on the spatial distribution of infant mortality in the Lyon metropolitan area, in France. METHODS: All infant deaths (n = 715) occurring between 2000 and 2009 were geocoded at census block level. Each census block was assigned multi-component socio-economic characteristics and Lden levels, which measure exposure to noise. Using a spatial-scan statistic, we examined whether there were significant clusters of high risk of infant mortality according to neighbourhood characteristics. RESULTS: Our results highlight the fact that infant mortality is non-randomly distributed spatially, with clusters of high risk in the south-east of the Lyon metropolitan area (RR = 1.44; p = 0.09). After adjustments for socio-economic characteristics and noise levels, this cluster disappears or shifts according to in line with different scenarios, suggesting that noise and socio-economic characteristics can partially explain the spatial distribution of infant mortality. CONCLUSION: Our findings show that noise does have an impact on the spatial distribution of mortality after adjustments for socio-economic characteristics. A link between noise and infant mortality seems plausible in view of the three hypothetical, non-exclusive, pathways we propose in our conceptual framework: (i) a psychological pathway, (ii) a physiological disruption process and (iii) an unhealthy behaviours pathway. The lack of studies makes it is difficult to compare our findings with others. They require further research for confirmation and interpretation.
ISSN: 1476-069X

Droits : info:eu-repo/semantics/OpenAccess
inserm-00924503
http://www.hal.inserm.fr/inserm-00924503
http://www.hal.inserm.fr/inserm-00924503/document
http://www.hal.inserm.fr/inserm-00924503/file/1476-069X-12-109.pdf
PUBMED : 24341620

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Plasma membrane is an early target of polycyclic aromatic hydrocarbons (PAH). We previously showed that the PAH prototype, benzo[a]pyrene (B[a]P), triggers apoptosis via DNA damage-induced p53 activation (genotoxic pathway) and via remodeling of the membrane cholesterol-rich microdomains called lipid rafts, leading to changes in pH homeostasis (non-genotoxic pathway). As omega-3 (n-3) fatty acids can affect membrane composition and function or hamper in vivo PAH genotoxicity, we hypothesized that addition of physiologically relevant levels of polyunsaturated n-3 fatty acids (PUFAs) might interfere with B[a]P-induced toxicity. The effects of two major PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were tested on B[a]P cytotoxicity in the liver epithelial cell line F258. Both PUFAs reduced B[a]P-induced apoptosis. Surprisingly, pre-treatment with DHA increased the formation of reactive B[a]P metabolites, resulting in higher levels of B[a]P-DNA adducts. EPA had no apparent effect on B[a]P metabolism or related DNA damage. EPA and DHA prevented B[a]P-induced apoptotic alkalinization by affecting Na(+)/H(+) exchanger 1 activity. Thus, the inhibitory effects of omega-3 fatty acids on B[a]P-induced apoptosis involve a non-genotoxic pathway associated with plasma membrane remodeling. Our results suggest that dietary omega-3 fatty acids may have marked effects on the biological consequences of PAH exposure.
ISSN: 0009-2797

hal-00950341
https://hal.archives-ouvertes.fr/hal-00950341
https://hal.archives-ouvertes.fr/hal-00950341/document
https://hal.archives-ouvertes.fr/hal-00950341/file/DENDELE_et_al_2013-unmarked.pdf
PUBMED : 24246761

Éditeur(s) : Pergamon-elsevier Science Ltd
Résumé : The present work aimed at better understanding metal and metalloid bioaccumulation in the edible Pacific blue shrimp Litopenaeus stylirostris, using both laboratory and field approaches. In the laboratory, the bioaccumulation kinetics of Ag, Cd, Co, Cr, and Zn have been investigated in shrimp exposed via seawater and food, using the corresponding gamma-emitting radiotracers (Ag-110m, Cd-109, Co-57, Cr-51, and Zn-65) and highly sensitive nuclear detection techniques. Results showed that hepatopancreas and intestine concentrated the metals to the highest extent among the blue shrimp organs and tissues. Moulting was found to play a non negligible detoxification role for Co, Cr and, to a lesser extent, Zn. Metal retention by L stylirostris widely varied (from a few days to several months), according to the element and exposure pathway considered (a given metal was usually less strongly retained when ingested with food than when it was taken up from the dissolved phase). In the field study, Ag, As, Cd, Co, Cr, Cu, Mn, Ni, and Zn were analysed in shrimp collected from a New Caledonian aquaculture pond. Metal concentrations in the shrimp muscles were generally relatively low and results confirmed the role played by the digestive organs and tissues in the bioaccumulation/storage/detoxification of metals in the Pacific blue shrimp. Preliminary risk considerations indicate that consumption of the shrimp farmed in New Caledonia is not of particular concern for human health. (C) 2010 Elsevier Ltd. All rights reserved.
Marine Pollution Bulletin (0025-326X) (Pergamon-elsevier Science Ltd), 2010 , Vol. 61 , N. 7-12 , P. 576-584

Droits : 2010 Elsevier Ltd All rights reserved.
http://archimer.ifremer.fr/doc/00014/12528/9869.pdf
DOI:10.1016/j.marpolbul.2010.06.035
http://archimer.ifremer.fr/doc/00014/12528/

Éditeur(s) : HAL CCSD
Résumé : Food-grade dairy propionibacteria release beneficial short chain fatty acids (SCFAs), folic acid and cobalamin. They induce apoptosis via the mitochondrial death pathway. We investigated their synergy with drugs used in gastric and colorectal cancer.Fermented milk containing propionibacteria and SCFAS acetate and propionate, as well as its cell-free supernatant, induced apoptosis in gastric HGT-1 and colic HT-29. Characterization of cells revealed apoptosis induction evidenced by chromatin condensation, DNA laddering, emergence of a subG1 population, phosphatidylserine exposure at the plasma membrane outer leaflet and cytochrome c release. Interestingly, the fermented milk was shown to potentiate the cytotoxic effect of molecules used in cancer chemotherapy, camptothecin and TRAIL (TNF Related Apoptosis Inducing Ligand).These results open new perspectives in the field of colon cancer cells prevention and/or treatment. Such a fermented product, or the propionibacterium alone, may be proposed as a food supplement to enhance the effects of anticancer treatments.
Les bactéries propioniques laitières produisent des acides gras volatils (AGV), acide folique et cobalamine, composés bénéfiques. Elles induisent l’apoptose via la voie mitochondriale. Nous avons recherché leur synergie avec des drogues utilisées dans le cancer gastrique ou colique.Un lait fermenté contenant des bactéries propioniques et les AGVs propionate et acétate a induit l’apoptose de cellules gastriques HGT-1 et coliques HT-29. L’étude des cellules a révélé l’induction de l’apoptose : condensation de la chromatine, fragmentation de l’ADN, l’émergence d’une population subG1, l’externalisation des phosphatidylserines et le relargage du cytochrome c. De manière intéressante, le lait fermenté a potentialisé les effets cytotoxiques de molécules utilisées en chimiothérapie, camptothécine et TRAIL (TNF Related Apoptosis Inducing Ligand).Ces résultats ouvrent de nouvelles perspectives dans le domaine du traitement ou de la prévention des cancers digestifs. Un tel produit fermenté, ou les propionibactéries seules, pourrait être proposé comme supplément alimentaire pour augmenter l’efficacité de traitements anti-cancéreux.
5. Colloque Intenational Molécules & Ingrédients Santé
Quimper, France

hal-01204307
https://hal.archives-ouvertes.fr/hal-01204307
PRODINRA : 261444

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Herbicides are generally the most extensively used of the pesticides applied to agricultural crops. However, the literature contains little evidence useful in assessing the potential sources of the general population's exposure to herbicides, including by residential proximity to crops.The objective of this study was to take advantage of data from the PELAGIE mother–child cohort to identify the main determinants of the body burden of exposure to the chloroacetanilide and triazine herbicides commonly used on corn crops in Brittany, France, before 2006. Urine samples from a randomly selected subcohort of women in the first trimester of pregnancy (n=579) were assayed for herbicide metabolites. The residential exposure resulting from proximity to corn crops was assessed with satellite-image-based scores combined with meteorological data. Data on diet, drinking tap water (from the public water supply), occupations, and household herbicide use were collected by questionnaires.Herbicides were quantified in 5.3% to 39.7% of urine samples. Alachlor and acetochlor were found most frequently in the urine of women living in rural areas. The presence of dealkylated triazine metabolites in urine samples was positively associated with residential proximity to corn crops (OR=1.38, 95% CI: 1.05–1.80). Urinary metabolites of both atrazine and dealkylated triazine were correlated with tap water consumption (OR=2.94, 1.09–7.90, and OR=1.82, 1.10–3.03, respectively); hydroxylated triazine metabolites were correlated with fish intake (OR=1.48, 1.09–1.99).This study reinforces previous results that suggest that environmental contamination resulting from agricultural activities may contribute to the general population's exposure to herbicides.
ISSN: 0160-4120

hal-01107546
https://hal.archives-ouvertes.fr/hal-01107546
DOI : 10.1016/j.envint.2013.10.010
PUBMED : 24246238

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The heterodimeric L-type amino acid transporter (LAT) 1/ CD98hc is overexpressed in lung cancers with a poor prognosis factor. Factors that contribute to LAT1/CD98hc overexpression in lung cells remain however to be determined, but the implication of atmospheric pollution can be suspected. The present study was therefore designed to analyze the effects of diesel exhaust particle (DEP) extract (DEPe) on LAT1/CD98hc expression in bronchial epithelial BEAS-2B cells. Exposure to DEPe up-regulated LAT1 and CD98hc mRNA levels in a concentration-dependent manner, with DEPe EC50 values (around 0.2 μg/mL) relevant to environmental situations. DEPe concomitantly induced LAT1/CD98hc protein expression and LAT1-mediated leucine accumulation in BEAS-2B cells. Inhibition of the aryl hydrocarbon receptor (AhR) pathway through the use of a chemical AhR antagonist or the siRNA-mediated silencing of AhR expression was next found to prevent DEPe-mediated induction of LAT1/CD98hc, indicating that this regulation depends on AhR, known to be activated by major chemical DEP components like polycyclic aromatic hydrocarbons. DEPe exposure was finally shown to induce mRNA expression and activity of matrix metalloproteinase (MMP)-2 in BEAS-2B cells, in a CD98hc/focal adhesion kinase (FAK)/extracellular regulated kinase (ERK) manner, thus suggesting that DEPe-mediated induction of CD98hc triggers activation of the integrin/FAK/ERK signaling pathway known to be involved in MMP-2 regulation. Taken together, these data demonstrate that exposure to DEPe induces functional overexpression of the amino acid transporter LAT1/CD98h in lung cells. Such a regulation may participate to pulmonary carcinogenic effects of DEPs, owing to the well-documented contribution of LAT1 and CD98hc to cancer development.
ISSN: 0041-008X

hal-01237095
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237095
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237095/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237095/file/Aryl%20hydrocarbon%20receptor-dependent%20up-regulation_accepted.pdf
DOI : 10.1016/j.taap.2015.11.014

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Numerous field studies highlighted the capacities of marine sponges to bioaccumulate trace elements and assessed their potential as biomonitors of the marine environment. Experimental works demonstrated that dissolved metals and radionuclides can be taken up directly by sponge tissues but, to the best of our knowledge, little is known on the contribution of the dietary pathway through the consumption of contaminated bacteria considered as one of the trophic source in sponge diet. Objectives of this work are to study trophic transfer of radiotracers 110mAg, 241Am, 109Cd, 57Co, 134Cs, 54Mn and 65Zn from the marine bacteria Pseudomonas stutzeri to the Mediterranean sponges Aplysina cavernicola and Ircinia oros. P. stutzeri efficiently bioaccumulated trace elements in our culture experimental conditions with CF comprised between 105 and 107 after 48 hours of growth in radiolabeled medium. When fed with these radiolabelled bacteria, A. cavernicola took up around 60% of radiotracers accumulated in trophic source except 134Cs for which only 8% has been transferred from bacteria to sponge. Contrasting to this, I. oros retained only 7% of 110mAg, 109Cd and 65Zn counted in bacteria, but retained 2-fold longer accumulated metals in its tissues. The sponge inter-specific differences of accumulation and depuration following a trophic exposure are discussed with respect to the structure and the clearance capacities of each species.
ISSN: 0045-6535

hal-01217273
https://hal.archives-ouvertes.fr/hal-01217273
https://hal.archives-ouvertes.fr/hal-01217273/document
https://hal.archives-ouvertes.fr/hal-01217273/file/Pub%20Bacteria%20CHEM_HAL.pdf
DOI : 10.1016/j.chemosphere.2015.10.046

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Lung diseases are aggravated by exposure to diesel exhaust particles (DEPs) found in air pollution. Macrophages are thought to play a crucial role in lung immune response to these pollutants, even if the mechanisms involved remain incompletely characterized. In the present study, we demonstrated that classically and alternative human macrophages (MΦ) exhibited increased secretion of PDGF-B in response to DEP extract (DEPe). This occurred via aryl hydrocarbon receptor (AhR)-activation because DEPe-induced PDGF-B overexpression was abrogated after AhR expression knock-down by RNA interference, in both M1 and M2 polarizing MΦ. In addition, TCDD and benzo(a)pyrene, two potent AhR ligands, also significantly increased mRNA expression of PDGF-B in M1 MΦ, whereas some weak ligands of AhR did not. We next evaluated the impact of conditioned media (CM) from MΦ culture exposed to DEPe or of recombinant PDGF-B onto lung fibroblast proliferation. The tyrosine kinase inhibitor, AG1295, prevents phosphorylations of PDGF-Rβ, AKT and ERK1/2 and the proliferation of MRC5 fibroblasts induced by recombinant PDGF-B and by CM from M1 polarizing MΦ, strongly suggesting that the PDGF-BB secreted by DEPe-exposed MΦ is sufficient to activate the PDGF-Rβ pathway of human lung fibroblasts. In conclusion, we demonstrated that human MΦ, whatever their polarization status, secrete PDGF-B in response to DEPe and that PDGF-B is a target gene of AhR. Therefore, induction of PDGF-B by DEP may participate in the deleterious effects towards human health triggered by such environmental urban contaminants.
ISSN: 0041-008X

hal-01146840
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146840
DOI : 10.1016/j.taap.2015.04.007
PUBMED : 25896968

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Multiple chemicals are emitted in residential accommodation. Aggregate Daily Doses (ADD) (ng/kg-bw/d) were estimated for 32 semivolatile organic compounds (SVOCs) of different chemical families that are frequently detected in French dwellings in both air and settled dust. Daily doses were determined using steady-state models for the population, categorized into 11 age groups covering birth to age 30. Three routes of exposure were taken into account: dust ingestion, inhalation (gaseous and particulate phases) and dermal contact with the gaseous phase of air. Contamination levels were preferentially retrieved from large, nationwide representative datasets. A two-dimensional probabilistic approach was used to assess parametric uncertainty and identify the most influential factors. For children aged 2 to 3 years, ADD estimates spanned orders of magnitude, with median values ranging from 8.7 pg/kg-bw/d for 2,2′,3,4,4′-pentabromodiphenylether (BDE 85) to 1.3 μg/kg-bw/d for di-isobutyl phthalate (DiBP). Inhalation, ingestion and dermal pathway contributed at varying levels, and depending on compound, air was the dominant medium for 28 of the 32 compounds (either by inhalation or dermal contact). Indoor exposure estimate variance was mainly driven by indoor contamination variability, and secondarily by uncertainty in physical and chemical parameters. These findings lend support to the call for cumulative risk assessment of indoor SVOCs.
ISSN: 0160-4120

hal-01635777
https://hal.archives-ouvertes.fr/hal-01635777
https://hal.archives-ouvertes.fr/hal-01635777/document
https://hal.archives-ouvertes.fr/hal-01635777/file/Article_Expo_Pelletier_Manuscript%20Env%20Int%20rev2.pdf
DOI : 10.1016/j.envint.2017.08.024

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Diesel exhaust particles (DEPs) are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe) may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC) uptake transporters organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC) efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 μg/mL and relevant to environmental exposure situations. By contrast, 25 μg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT) 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP), whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP). Treatment by 25 μg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a reference activator of the aryl hydrocarbon receptor (AhR) pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute to their systemic effects through impairing hepatic transport of endogenous compound or drug substrates of these transporters.
ISSN: 1932-6203

Droits : http://creativecommons.org/licenses/by/
hal-01138535
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01138535
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01138535/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01138535/file/Regulation%20of%20human%20hepatic%20drug.pdf
DOI : 10.1371/journal.pone.0121232

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
The extensive use of tyrosine kinase inhibitors (TKI's) in hematology and oncology has shown that these drugs have a significant potential for drug-drug interactions. Since these drugs have a rather low therapeutic window, some drug interactions are of particular clinical relevance either on drug toxicity or on patient's response. Significant interactions occur with concomitant use of acid-suppressive therapy leading to a decreased oral bioavailability. However, such interactions are drug dependent according to their solubility pattern and to the duration of action of acid-suppressive therapy, which is coprescribed. Significant interactions occur by inhibition or induction of CYP450 3A4 which is the main metabolic pathway of TKIs. However, minor metabolic pathways should also be paid attention to. Interactions involving efflux and influx transporters should also be considered occurring for some TKIs. Genetic polymorphism in drug metabolism as well as in drug transport is a factor of variability in drug exposure, which could modulate the magnitude of drug-drug interactions (DDIs). It should be noticed that TKIs can also be at the origin of drug interactions by altering the pharmacokinetics of coprescribed drugs. Since cancer patients are given many drugs either for supportive care or for the treatment of drug toxicity, and to the fact that the oldest patients are polymedicated, a clear understanding of DDIs with TKIs is of interest. The objectives of this review are to provide an overview of the mechanisms of DDIs with TKIs and to provide to physicians and pharmacists recommendations to manage these DDIs in their clinical practice.
ISSN: 0278-0232

hal-01616064
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616064
DOI : 10.1002/hon.2335
PUBMED : 27925256