Éditeur(s) : HAL CCSD
Résumé : Semi-volatile organic compounds (SVOCs) are widely present in indoor environments and are suspected to be repro- or neurotoxic but little is known on the health impact on SVOC mixtures. The objective of this work is to derive cumulative toxicity indicators for SVOCs detected in French dwellings in carrying forward a cumulative health risk assessment. SVOCs were grouped according to their repro- and neurotoxic common modes of action (i.e. decrease in serum testosterone concentrations, decrease in neuronal viability). Benchmark doses (BMDs) were then estimated by modeling dose-response relationships from scientific literature (Hill models, PROAST, RIVM). Comparable BMDs were estimated only for 6 of the 19 reprotoxic SVOCs which are responsible to 10 or 50% decrease in testosterone in adult male rats orally exposed. Estimated relative potency factors (RPFs) from BMDs are similar according to the response level (from 1600 for the B(a)P to 0.1 for the BBP), excepted for bisphenol A moving from 7E+6 to 180. For in vitro neuronal death, BMDs were estimated for 13 neurotoxic SVOCs using data from different cell lines and species. BMDs equivalent to a 10% of response range from 0.07 (PCB-153) to 95 µM (diazinon). The originality of this work is the grouping of compounds from different chemical families which we are really exposed to. BMDs estimation from published data was possible but many methodological limitations lead us to put forward recommendations especially on the standardization of experimental protocols and the availability of results in adapted format for dose-response relationship modeling.
Les composés organiques semi volatils (COSV) sont largement présents dans les environnements intérieurs et sont suspectés d’être repro- ou neurotoxiques, mais peu de données sont disponibles quant à leur toxicité en mélanges. L’objectif de cette thèse est de proposer des indicateurs de toxicité cumulés pour les COSV détectés dans les logements français, dans un cadre d’évaluation des risques sanitaires cumulés. Les COSV ont été regroupés en fonction de leurs modes d’action communs, en lien avec les effets reprotoxiques (diminution de la concentration de testostérone sérique) et neurotoxiques (diminution de la viabilité neuronale). Des benchmark doses (BMD) ont ensuite été estimées par modélisation (modèle de Hill, PROAST, RIVM) des relations dose-réponse de la littérature décrivant la réponse d’intérêt. Des BMD comparables ont pu être estimées seulement pour 6 des 19 COSV reprotoxiques induisant une diminution de testostérone de 10 ou 50 % chez le rat adulte exposé par voie orale. Les facteurs de toxicité relatifs (RPF) estimés à partir des BMD sont sensiblement les mêmes en fonction du niveau de réponse (de 1600 pour le B(a)P à 0,1 pour le BBP), excepté pour le biphénol A qui passe de 7E+6 à 180. Considérant la mort neuronale in vitro, des BMD ont pu être estimées pour 13 COSV neurotoxiques, à partir de données provenant de différentes lignées et espèces. Les BMD équivalent à un niveau de réponse de 10 % s’échelonnent de 0,07 (PCB-153) à 95 µM (diazinon). L’originalité de ce travail repose sur le regroupement de composés de familles chimiques différentes qui constituent des contaminations réelles de notre environnement. Si l’estimation des quelques BMD a été possible à partir des données de la littérature, de nombreuses limites méthodologiques conduisent à émettre des recommandations en particulier sur la standardisation des protocoles expérimentaux et la disponibilité des résultats sous une forme adaptée à la modélisation de la relation dose-réponse.
https://tel.archives-ouvertes.fr/tel-01308535

NNT : 2015REN1B019
tel-01308535
https://tel.archives-ouvertes.fr/tel-01308535
https://tel.archives-ouvertes.fr/tel-01308535/document
https://tel.archives-ouvertes.fr/tel-01308535/file/Kevin_Fournier-.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: Semi Volatile Organic Compounds (SVOCs) are contaminants commonly found in dwellings as a result of their use as plasticizers, flame retardants, or pesticides in building materials and consumer products. Many SVOCs are suspected of being neurotoxic, based on mammal experimentation (impairment of locomotor activity, spatial learning/memory or behavioral changes), raising the question of cumulative risk assessment. The aim of this work is to estimate the relative toxicity of such SVOCs, based on neuronal death. METHOD: SVOCs fulfilling the following conditions were included: detection frequency >10% in dwellings, availability of data on effects or mechanism of action for neurotoxicity, and availability of dose-response relationships based on cell viability assays as a proxy of neuronal death. Benchmark concentration values (BMC) were estimated using a Hill model, and compared to assess relative toxicity. RESULTS: Of the 58 SVOCs selected, 28 were suspected of being neurotoxic in mammals, and 21 have been documented as inducing a decrease in cell viability in vitro. 13 have at least one dose-response relationship that can be used to derive a BMC based on a 10% fall in neuronal viability. Based on this in vitro endpoint, PCB-153 appeared to be the most toxic compound, having the lowest BMC10 (0.072μM) and diazinon the least toxic compound, having the highest BMC10 (94.35μM). We showed that experimental designs (in particular choice of cell lines) had a significant influence on BMC calculation. CONCLUSION: For the first time, the relative in vitro toxicity of 13 indoor contaminants belonging to different chemical families has been assessed on the basis of neuronal cell viability. Lack of comparable toxicity datasets limits the number of SVOCs that can be included. More standardized protocols in terms of cell lines, species and exposure duration should be developed with a view to cumulative risk assessment.
Toxicology Letters

hal-01579605
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579605
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579605/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579605/file/Fournier%20et%20al.%20-%20Relative%20toxicity%20for%20indoor%20semi%20volatile%20organic.pdf
DOI : 10.1016/j.toxlet.2017.07.875

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
We propose a new geometric approach to describe the qualitative dynamics of chemical reactions networks. By this method we identify metastable regimes, defined as low dimensional regions of the phase space close to which the dynamics is much slower compared to the rest of the phase space. These metastable regimes depend on the network topology and on the orders of magnitude of the kinetic parameters. Benchmarking of the method on a computational biology model repository suggests that the number of metastable regimes is sub-exponential in the number of variables and equations. The dynamics of the network can be described as a sequence of jumps from one metastable regime to another. We show that a geometrically computed con-nectivity graph restricts the set of possible jumps. We also provide finite state machine (Markov chain) models for such dynamic changes. Applied to signal transduction models, our approach unravels dynamical and functional * corresponding author capacities of signalling pathways, as well as parameters responsible for speci-ficity of the pathway response. In particular, for a model of TGFβ signalling, we find that the ratio of TGFBR2 to TGFBR1 receptors concentrations can be used to discriminate between metastable regimes. Using expression data from the NCI60 panel of human tumor cell lines, we show that aggressive and non-aggressive tumour cell lines function in different metastable regimes and can be distinguished by measuring the relative concentrations of receptors of the two types.
ISSN: 0303-2647

hal-01379033
https://hal.inria.fr/hal-01379033
https://hal.inria.fr/hal-01379033/document
https://hal.inria.fr/hal-01379033/file/Samal_et_al_Biosystems_final.pdf
DOI : 10.1016/j.biosystems.2016.07.004

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10= 7.72E-07 mg/kg bw/d; RPF10= 7033679); for 50%, benzo[a]pyrene (BMD50= 0.030 mg/kg bw/d; RPF50= 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50= 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data.
ISSN: 0273-2300

hal-01237085
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085/file/Multiple%20exposures%20to%20indoor%20contaminants_accepted.pdf
DOI : 10.1016/j.yrtph.2015.11.017