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. / 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.

PACAP and VIP have prominent effects on cardiac function in several species, but little is known about their influence on the murine heart. Accordingly, we evaluated the expression of PACAP/VIP receptors in mouse heart and the response of isolated atria to peptide agonists. Quantitative PCR demonstrated that PAC1, VPAC1, and VPAC2 receptor mRNAs are present throughout the mouse heart. Expression of all three receptor transcripts was low, PAC1 being the lowest. No regional differences in expression were detected for individual receptor mRNAs after normalization to L32. Pharmacological effects of PACAP-27, VIP, and the selective PAC1 agonist maxadilan were evaluated in isolated, spontaneously beating atria from C57BL/6 mice of either sex. Incremental additions of PACAP-27 at 1 min intervals caused a concentration-dependent tachycardia with a log EC50=-9.08±0.15 M (n=7) and a maximum of 96.3±5.9% above baseline heart rate. VIP and maxadilan also caused tachycardia but their potencies were about two orders of magnitude less. Increasing the dosing interval to 5 min caused a leftward shift of the concentration-response curve to maxadilan but no changes in the curves for PACAP-27 or VIP. Under this condition, neither the potency nor the efficacy of maxadilan differed from those of PACAP-27. Neither PACAP-27 nor maxadilan caused tachyphylaxis, and maximal responses to maxadilan were maintained for at least 2 h. We conclude that all three VIP/PACAP family receptors are expressed by mouse cardiac tissue, but only PAC1 receptors mediate positive chronotropic responses to PACAP-27 and VIP.

PACAP and VIP have prominent effects on cardiac function in several species, but little is known about their influence on the murine heart. Accordingly, we evaluated the expression of PACAP/VIP receptors in mouse heart and the response of isolated atria to peptide agonists. Quantitative PCR demonstrated that PAC1, VPAC1, and VPAC2 receptor mRNAs are present throughout the mouse heart. Expression of all three receptor transcripts was low, PAC1 being the lowest. No regional differences in expression were detected for individual receptor mRNAs after normalization to L32. Pharmacological effects of PACAP-27, VIP, and the selective PAC1 agonist maxadilan were evaluated in isolated, spontaneously beating atria from C57BL/6 mice of either sex. Incremental additions of PACAP-27 at 1 min intervals caused a concentration-dependent tachycardia with a log EC50=-9.08±0.15 M (n=7) and a maximum of 96.3±5.9% above baseline heart rate. VIP and maxadilan also caused tachycardia but their potencies were about two orders of magnitude less. Increasing the dosing interval to 5 min caused a leftward shift of the concentration-response curve to maxadilan but no changes in the curves for PACAP-27 or VIP. Under this condition, neither the potency nor the efficacy of maxadilan differed from those of PACAP-27. Neither PACAP-27 nor maxadilan caused tachyphylaxis, and maximal responses to maxadilan were maintained for at least 2 h. We conclude that all three VIP/PACAP family receptors are expressed by mouse cardiac tissue, but only PAC1 receptors mediate positive chronotropic responses to PACAP-27 and VIP.

In this dissertation we first consider a parallel linear model with correlated dual responses on a symmetric compact design region and construct locally optimal designs for estimating the location-shift parameter. These locally optimal designs are variant under linear transformation of the design space and depend on the correlation between the dual responses in an interesting and sensitive way. Subsequently, minimax and maximin efficient designs for estimating the location-shift parameter are derived. A comparison of the behavior of efficiencies between the minimax and maximin efficient designs relative to locally optimal designs is also provided. Both minimax or maximin efficient designs have advantage in terms of estimating efficiencies in different situations. Thirdly, we consider a linear regression model with a one-dimensional control variable x and an m-dimensional response variable y=(y_1,...,y_m). The components of y are correlated with a known covariance matrix. The calibration problem discussed here is based on the assumed regression model. It is of interest to obtain a suitable estimation of the corresponding x for a given target T=(T_1,...,T_m) on the expected responses. Due to the fact that there is more than one target value to be achieved in the multiresponse case, the m expected responses may meet their target values at different respective control values. Consideration includes the deviation of the expected response E(y_i) from its corresponding target value T_i for each component and the optimal value of calibration point x, say x_0, is considered to be the one which minimizes the weighted sum of squares of such deviations within the range of x. The objective of this study is to find a locally optimal design for estimating x_0, which minimizes the mean square error of the difference between x_0 and its estimator. It shows the optimality criterion is approximately equivalent to a c-criterion under certain conditions and explicit solutions with dual responses under linear and quadratic polynomial regressions are obtained.