L'exposition aux mélanges de contaminants (environnementaux, alimentaires ou thérapeutiques) soulève de nombreuses interrogations et inquiétudes vis-à-vis des probabilités d'interactions toxicocinétiques et toxicodynamiques. Une telle coexposition peut influencer le mode d’action des composants du cocktail et donc de leur toxicité, suite à un accroissement de leurs concentrations internes. Le bisphénol A (4 dihydroxy-2,2-diphenylpropane) est un contaminant chimique répandu de manière ubiquitaire dans notre environnement, largement utilisé dans la fabrication des plastiques avec l’un des plus grands volumes de production à l’échelle mondiale. Il est un perturbateur endocrinien par excellence de type œstrogèno-mimétique. Cette molécule est biotransformée en métabolites non toxiques par un processus de glucuronidation. L'exposition concomitante à plusieurs xénobiotiques peut induire à la baisse le taux de glucuronidation du polluant chimique d'intérêt, entre autres la co-exposition avec des médicaments. Puisque la consommation de produits thérapeutiques est un phénomène grandissant dans la population, la possibilité d’une exposition simultanée est d’autant plus grande et forte. Sachant que l'inhibition métabolique est le mécanisme d'interaction le plus plausible pouvant aboutir à une hausse des niveaux internes ainsi qu’à une modulation de la toxicité prévue, la présente étude visait d'abord à confirmer et caractériser ce type d'interactions métaboliques entre le bisphénol A et le naproxène, qui est un anti-inflammatoire non stéroïdiennes (AINS), sur l'ensemble d'un organe intact en utilisant le système de foie de rat isolé et perfusé (IPRL). Elle visait ensuite à déterminer la cinétique enzymatique de chacune de ces deux substances, seule puis en mélange binaire. Dans un second temps, nous avons évalué aussi l’influence de la présence d'albumine sur la cinétique métabolique et le comportement de ces deux substances étudiées en suivant le même modèle de perfusion in vivo au niveau du foie de rat. Les constantes métaboliques ont été déterminées par régression non linéaire. Les métabolismes du BPA et du NAP seuls ont montré une cinétique saturable avec une vélocité maximale (Vmax) de 8.9 nmol/min/ mg prot de foie et une constante d'affinité de l'enzyme pour le substrat (Km) de 51.6 μM pour le BPA et de 3 nmol/min/mg prot de foie et 149.2 μM pour le NAP. L'analyse des expositions combinées suggère une inhibition compétitive partielle du métabolisme du BPA par le NAP avec une valeur de Ki estimée à 0.3542 μM. Les résultats obtenus montrent que l’analyse de risque pour les polluants environnementaux doit donc prendre en considération la consommation des produits pharmaceutiques comme facteur pouvant accroitre le niveau interne lors d’une exposition donnée. Ces données in vivo sur les interactions métaboliques pourraient être intégrées dans un modèle pharmacocinétique à base physiologique (PBPK) pour prédire les conséquences toxicococinétique (TK) de l'exposition d'un individu à ces mélanges chimiques. / Exposure to mixtures of contaminants (environmental, alimentary or therapeutic) poses many questions and concerns about the probability of toxicokinetic and toxicodynamic interactions. Such co-exposure may influence the mode of action of the cocktail of components and therefore their toxicity, as a result of an increase of their internal concentrations. Bisphenol A (2,2-dihydroxy-4 diphenylpropane) is a ubiquitous chemical contaminant in our environment, widely used in the manufacture of plastics, with one of the largest production volumes globally. It is an endocrine disruptor of oestrogen-mimetic type. This molecule is metabolized into non-toxic metabolites by glucuronidation process. Several factors including the co-exposure to other xenobiotics may reduce the glucuronidation rate of the chemical pollutant of interest, such as a co-exposure with drugs. Given that the consumption of therapeutic products is a growing phenomenon in the population, simultaneous exposures of pollutants with medicinal drugs are becoming a concern for health risk assessment. Knowing that metabolic inhibition is the most plausible mechanism of interaction that could result in an increase of the internal levels and a modulation of the expected toxicity, the present study aimed at confirming and characterizing this type of metabolic interactions between bisphenol A and naproxen, which is a non-steroidal anti-inflammatory drug (NSAID), on the set of an intact organ using isolated and perfused rat liver system (IPRL). The study also served to determine the enzyme kinetics metabolism of each substance alone and in binary mixture. In a second step, we also evaluated the influence of the presence of albumin on the metabolic kinetics and behavior of the two substances studied using the same in vivo perfusion model of rat liver. Metabolic constants were determined by nonlinear regression. The metabolism of BPA and NAP alone demonstrated saturable kinetics with maximal velocity (Vmax) and affinity constant (Km) equal to 8.9 nmol/min/mg prot liver and 51.6 μM for BPA, and 3 nmol/min/mg prot liver and 149.2 μM for NAP. The analysis of combined exposures suggests a partial competitive inhibition of BPA metabolism by NAP with a Ki value estimated at 0.3542 µM. From these results, it appears that the risk assessment of environmental pollutants must therefore consider the consumption of pharmaceutical products as an important agent that can increase the internal levels for a given exposure. Accordingly, these in vivo data on metabolic interactions can be incorporated into a physiologically based pharmacokinetic models (PBPK) to predict the toxicokinetic consequences (TK) of the exposure by an individual to these chemical mixtures.

Over the last decades, there has been much attention on air quality, especially in urban environments. A significant factor effecting the air quality in the urban environment is airborne particulate matter (PM). Long-term exposure to PM causes increased risk for heart disease, decreased lung function, exacerbation of asthma, and lung cancer. Therefore, many countries have implemented exposure limits to the concentration of ambient PM in the urban environments. The toxicity of PM is dependent on several factors such as chemical composition, shape, adsorbed materials, and particle sizes (usually divided in ultrafine, fine and coarse particles). However, the relationship between different PM properties and developing health hazards are not clear. Therefore, further studies to investigate different properties of PM may contribute to understanding the influence of PM on human health.  In the present work, different novel methods to investigate sampled airborne PM and to investigate potential health effects have been used to increase the knowledge regarding street and wear particles. In study I, a sampling plan involving collecting one filter from Tapered Element Oscillating Microbalance (TEOM) monitoring stations used for Environmental monitoring each month for 20 months were developed. Particles on the filters were extracted into a suspension. TEOM particles were then studied with respect to constituents and variables that reflect their toxicity. The constituent and toxicity was found to be spatial and seasonal dependent. As a follow-up, in study II, TEOM filters from three geographical different cities were collected once a month for a year. The variation in particle mass measured with TEOM monitor, cadmium and lead contents, as well as endotoxin levels between locations and time points over the year was studied. The correlation between studied variables and biological effect was investigated. The results show that the concentration of metals and endotoxin in TEOM particles have no relationship to particle mass, while endotoxin levels coincided with pro-inflammatory response. These studies show that results from analyzing different variables on obtained particles from TEOM filters in combination with information about the ambient particle concentration, could be helpful in the evaluation of differences in the risk of breathing air at various locations.  The dominant road traffic particle sources are wear particles from the road and tyre interface, and from vehicle brake pads. The particle concentrations are highest in cities with high traffic amounts and a high frequency of braking. There are a few cell studies that have investigated the toxicological and biological effect of these wear particles, but there is a lack of knowledge regarding their effect on tissue level. Furthermore, the knowledge about importance of rock materials in pavement is deficient. To mitigate these knowledge gaps, the effect of different wear particles from pavement and brake pad were tested using a model with isolated perfused rat lungs in study III. The wear particles from the pavement showed a significant decrease of tidal volume compared to unexposed controls. The largest effect were found with quartzite stone material. Wear particles from brakes instead showed a larger effect on released proinflammatory cytokines. The study shows that the toxic effect on lungs exposed to airborne particles can be investigated using repetitive measurements of tidal volume. Furthermore, the study shows that the choice of rock material in road pavements has the potential to affect the toxicity of road wear particles. This should be considered in environments where the concentrations and exposures are high. The brake particles showed a different effect than stone particles, indicating the need to differentiate wear particles from different sources in relation to health effects. In summary, the present work have investigated different aspects of airborne particles collected from streets as well as generated wear particles. These indicate different important aspects of the particles that may be of importance to better understand their health effects.