Approche multidisciplinaire pour l’amélioration de l’estimation de l’exposition aux sous-produits de désinfection de l’eau en milieu domestique et en piscine

La désinfection de l’eau de consommation et des piscines induit la formation de sous-produits (SPD) potentiellement nocifs pour la santé, parmi lesquels les trihalométhanes (THM), les acides haloacétiques (HAA) et les chloramines (CAM). La difficulté d’estimer l’exposition humaine à ces SPD empêche de cerner précisément les risques sanitaires possiblement associés (i.e., cancérigènes, reprotoxiques, irritatifs). Nos travaux s’articulent autour d’une méthodologie consistant à intégrer des données d’occurrence environnementales à des modèles toxicocinétiques à base physiologique (TCBP) pour améliorer les mesures de l’exposition aux SPD. Cette approche multidisciplinaire veut prendre en compte de manière aussi appropriée que possible les deux composantes majeures des variations de cette exposition : les variations spatio-temporelles des niveaux de contamination environnementale et l’impact des différences inter- et intra-individuelles sur les niveaux biologiques. Cette thèse, organisée en deux volets qui explorent chacun successivement des aspects environnemental et biologique de la problématique, vise à contribuer au développement de cette stratégie innovante d’estimation de l’exposition et, plus généralement, à des meilleures pratiques en la matière. Le premier volet de la thèse s’intéresse à l’exposition en milieu domestique (i.e., résultant de l’utilisation de l’eau potable au domicile) et est consacré au cas complexe des THM, les plus abondants et volatils des SPD, absorbables par ingestion mais aussi par inhalation et voie percutanée. Les articles I et II, constitutifs de ce volet, documentent spécifiquement la question des variations inter- et intra- journalières de présence des SPD en réseau et de leurs impacts sur les estimateurs de l’exposition biologique. Ils décrivent l’amplitude et la diversité des variations à court terme des niveaux environnementaux, présentent les difficultés à proposer une façon systématique et « épidémiologiquement » pratique de les modéliser et proposent, de manière originale, une évaluation des mésestimations, somme toute modestes, des mesures biologiques de l’exposition résultant de leurs non-prise en compte. Le deuxième volet de la thèse se penche sur l’exposition aux SPD en piscine, d’un intérêt grandissant au niveau international, et se restreint au cas jugé prioritaire des piscines publiques intérieures. Ce volet envisage, pour quantifier l’exposition dans ce contexte particulier, l’extension de l’approche méthodologique préconisée, élaborée originellement pour application dans un contexte domestique : d’abord, à travers une analyse approfondie des variations des niveaux de contamination (eau, air) des SPD en piscine en vue de les modéliser (article III); puis en examinant, dans le cas particulier du chloroforme, le THM le plus abondant, la possibilité d’utiliser la modélisation TCBP pour simuler des expositions en piscine (article IV). Les résultats mettent notamment en évidence la difficulté d’appréhender précisément la contamination environnementale autrement que par un échantillonnage in situ tandis que la modélisation TCBP apparait, sur le plan toxicologique, comme l’outil le plus pertinent à ce jour, notamment au regard des autres approches existantes, mais qu’il convient d’améliorer pour mieux prédire les niveaux d’exposition biologique. Finalement, ces travaux illustrent la pertinence et la nécessité d’une approche multidisciplinaire et intégratrice et suggère, sur cette base, les pistes à explorer en priorité pour mieux évaluer l’exposition aux SPD et, in fine, cerner véritablement les risques sanitaires qui en résultent.Disinfection of drinking and swimming pool waters disinfection is unavoidable but induces the formation of by-products (DBPs), such as trihalomethanes (THMs), haloacetic acids (HAAs) and chloramines (CAMs), that could be harmful to human health. The still challenging DBP exposure assessment prevent their suspected adverse effects (i.e., cancers, adverse pregnancy outcomes, irritations) to be clearly established. A methodology has been conceptualized which consists of integrating environmental occurrence data with physiologically based toxicokinetic (PBTK) modeling to improve DBP exposure assessment. It was designed to allow both spatial and temporal variations of the environmental contamination and the biological impacts of between- and within- individual differences to be accounted for. This thesis comprised of two parts. Each one investigates successively both environmental and biological aspects. The objective is to contribute to the development of an innovative integrated strategy and to the definition of best practices for DBP exposure assessment. The first part of the thesis, comprising papers I and II, focuses on household exposure (i.e., resulting from drinking water use at home) and on THMs, the most abundant and volatile DBPs that can be absorbed not only by ingestion but also by inhalation and dermal absorption. These two papers investigate particularly the short-term (day-to-day and within-day) variations of THM levels in the drinking water and then their impact on the internal exposure indicators. They described the amplitudes and the diversity of the environmental variations, failed to model them in a systematic and practical way for epidemiological purposes but assessed, for the first time, their impacts on the predicted biological levels which appeared quite low. The second part concerns the exposure to DBPs in swimming pool which is of a growing international interest. Only the allegedly worrying case of public indoor swimming pool was regarded. This section focuses on the feasibility of using the previously mentioned approach, which was first designed for dealing with household exposure, for DBP exposure assessment in swimming pools. First, Paper III investigated the occurrence and spatial and temporal variations of DBPs in both water and air of swimming pools to model them. Focusing on chloroform, the most abundant THM, Paper IV examined the ability and reliability of PBTK modeling to simulate various swimming pool exposure events and predict the resulting biological levels in individuals. The results show, among other things, the difficulty of explaining precisely the environmental contamination and point out the necessity to carry out a minimal in situ sampling to monitor the environmental levels of DBPs. Compared to other approaches, PBTK modeling is a powerful but still to be improved tool for predicting swimming pool exposure. Eventually, these works underline the relevance and the necessity of a multidisciplinary and integrating approach for better estimating exposure to DBPs and therefore health risks. Further issues that should be addressed are recommended

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Assessing Exposure to Chloroform in Swimming Pools Using Physiologically Based Toxicokinetic Modeling

Abstract This work examines the use of physiologically based toxicokinetic (PBTK) modeling to assess exposure to the most abundant disinfection by-product (DBP), chloroform (TCM), to be found in indoor swimming pools. Real exposure scenarios including environmental (water and air levels) and biological (alveolar air or blood levels) data extracted from the literature were simulated. Predicted biological data matched up well with the reported actual levels, thereby confirming the reliability of this approach. Relative contributions of inhalation and dermal absorption to the total body burden were estimated and compared to the inconsistent results of reported studies. The PBTK simulations served to explain this inconsistency, suggesting that the prevalence of each pathway depends on environmental concentrations and on the ratio between air and water levels in particular. Likewise, comparisons between 24-h typical household and typical 1-or 2-h swimming pool exposure scenarios point to the preponderance of the latter

Maternal Exposure to Drinking-water Chlorination By- products and Small-for-gestational-age Neonates

Background: There is concern about possible effects of disinfection by-products on reproductive outcomes. The purpose of this study was to evaluate the association between maternal exposure to chlorination by-products and the risk of delivering a small forgestational-age (SGA) neonate. Methods: We conducted a population-based case-control study in the Québec City (Canada) area. Term newborn cases with birth weights Ͻ10th percentile (n ϭ 571) were compared with 1925 term controls with birth weights Ն10th percentile. Concentrations of trihalomethanes and haloacetic acids in the water-distribution systems of participants were monitored during the study period, and a phone interview on maternal habits was completed within 3 months after childbirth. We estimated chlorination by-products ingestion during the last trimester of pregnancy and trihalomethanes doses resulting from inhalation and dermal exposure. We evaluated associations between chlorination by-products in utero exposure and SGA by means of unconditional logistic regression with control of potential confounders. Results: When total trihalomethanes and the 5 regulated haloacetic acids concentrations were divided into quartiles, no clear doseresponse relationship was found with SGA. However, increased risk was observed when haloacetic concentrations were above the fourth quartile and when either trihalomethanes or haloacetic acids concentrations were above current water standards (adjusted ORϭ 1.5 ͓95% confidence interval ϭ 1.1-1.9͔ and 1.4 ͓1.1-1.9͔, respectively). Inhalation and dermal absorption of trihalomethanes did no

Henkilöstön vaihtuvuus ja siihen liittyvät tekijät telemarkkinointialalla : case: Gainer Oy

Tämä opinnäytetyö toteutettiin toimeksiantosopimuksena Gainer Oy:lle, joka on toiminut telemarkkinoinnin alalla jo vuodesta 1984. Opinnäytetyön tutkimusstrategiaksi valittiin case study eli tapaustutkimus. Käytimme tutkimusmenetelmänä kvalitatiivista eli laadullista tutkimusta. Tavoitteenamme oli tutkia ja selvittää henkilöstön vaihtuvuutta ja siihen liittyviä tekijöitä alalla, jossa henkilöstön vaihtuvuus koetaan ongelmaksi. Teoriaosuudessa käsittelemme teoreettisen viitekehyksen liittyen työnantajan keinoihin vaikuttaa työntekijän sitouttamiseen. Tämä on jaettu kahteen osa-alueeseen, jotka ovat rekrytointi sekä työhyvinvointi ja osaamisen kehittäminen. Empiirisessä osiossa päädyimme käyttämään puolistrukturoitua teemahaastattelua, joka toteutettiin suurimmaksi osaksi puhelimitse sekä muutama haastattelu tehtiin kasvotusten. Teemahaastattelu valikoitui parhaimmaksi menetelmäksi johtuen aiheen moniulotteisuudesta. Avoimella haastattelulla emme olisi välttämättä saaneet merkittävää tietoa samassa mittakaavassa kuin puolistrukturoidulla mallilla. Opinnäytetyön tuloksena päädyimme esittämään toimeksiantajalle muutamia kehitysehdotuksia. Haastatteluista johdetuilla päätelmillä saatettaisiin parantaa rekrytoinnin onnistumista, joka osaltaan parantaa kannattavuutta niin tuloksellisesti, kuin henkilöstön resurssejakin säästäen. Kehitysehdotuksia muodostui myös muihin osa-alueisiin liittyen. Näillä on myös vaikutusta henkilöstön yleiseen työhyvinvointiin ja työssä jaksamiseen.This thesis was carried out as a commission agreement for Gainer Oy, which has operated in the field of telemarketing since 1984. Our study was carried out as a case study using qualitative approach as our research method. Our objective was to study personnel turnover and matters relating to it in a field where personnel turnover is seen as a problem. In the theoretical section of the study we deal with the theoretical frame of reference related to the employer's means to influence employee engagement. This is divided into two sections that are recruiting, and occupational health and development of skills. In the empirical part of our study, we ended up using half-structured theme interviews, which were mainly carried out by telephone. A few interviews were carried out face-to-face. Theme interview was selected to be the best method because of the multidimensionality of the subject. By using open interviews, we would not necessarily have received as much significant information as by using the half-structured model. As a result of our study, we presented a few development proposals for our client/commissioner. The conclusions drawn from the interviews may lead to more successful recruiting, which in turn improves viability both in terms of productivity and by saving the resources of the personnel. There were also other development proposals concerning other areas. The results of the study may also help to improve the general well-being at work and coping with one’s workload