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No / Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure–health effect relationships. The “exposome” concept encompasses the totality of exposures from conception onward, complementing the genome. Objectives: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the “early-life exposome.” Here we describe the general design of the project. Methods: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother–child pairs, and biomarkers will be measured in a subset of 1,200 mother–child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure–response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. Conclusions: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome.

According to the REACH regulation chemicals produced or imported to the European Union need to be assessed to manage the risk of potential hazard to human health and the environment. An increasing number of chemicals in commerce prompts the need for utilizing faster and cheaper alternative methods for this assessment, such as quantitative structure-activity or property relationships (QSARs or QSPRs). QSARs and QSPRs are models that seek correlation between data on chemicals molecular structure and a specific activity or property, such as environmental fate characteristics and (eco)toxicological effects. The aim of this thesis was to evaluate and develop models for the hazard assessment of industrial chemicals and the exposure assessment of pharmaceuticals. In focus were the identification of chemicals potentially demonstrating carcinogenic (C), mutagenic (M), or reprotoxic (R) effects, and endocrine disruption, the importance of metabolism in hazard identification, and the understanding of adsorption of ionisable chemicals to sludge with implications to the fate of pharmaceuticals in waste water treatment plants (WWTPs). Also, issues related to QSARs including consensus modelling, applicability domain, and ionisation of input structures were addressed. The main findings presented herein are as follows: QSARs were successful in identifying almost all carcinogens and most mutagens but worse in predicting chemicals toxic to reproduction. Metabolic activation is a key event in the identification of potentially hazardous chemicals, particularly for chemicals demonstrating estrogen (E) and transthyretin (T) related alterations of the endocrine system, but also for mutagens. The accuracy of currently available metabolism simulators is rather low for industrial chemicals. However, when combined with QSARs, the tool was found useful in identifying chemicals that demonstrated E- and T- related effects in vivo. We recommend using a consensus approach in final judgement about a compound’s toxicity that is to combine QSAR derived data to reach a consensus prediction. That is particularly useful for models based on data of slightly different molecular events or species. QSAR models need to have well-defined applicability domains (AD) to ensure their reliability, which can be reached by e.g. the conformal prediction (CP) method. By providing confidence metrics CP allows a better control over predictive boundaries of QSAR models than other distance-based AD methods. Pharmaceuticals can interact with sewage sludge by different intermolecular forces for which also the ionisation state has an impact. Developed models showed that sorption of neutral and positively-charged pharmaceuticals was mainly hydrophobicity-driven but also impacted by Pi-Pi and dipole-dipole forces. In contrast, negatively-charged molecules predominantly interacted via covalent bonding and ion-ion, ion-dipole, and dipole-dipole forces. Using ionised structures in multivariate modelling of sorption to sludge did not improve the model performance for positively- and negatively charged species but we noted an improvement for neutral chemicals that may be due to a more correct description of zwitterions.   Overall, the results provided insights on the current weaknesses and strengths of QSAR approaches in hazard and exposure assessment of chemicals. QSARs have a great potential to serve as commonly used tools in hazard identification to predict various responses demanded in chemical safety assessment. In combination with other tools they can provide fundaments for integrated testing strategies that gather and generate information about compound’s toxicity and provide insights of its potential hazard. The obtained results also show that QSARs can be utilized for pattern recognition that facilitates a better understanding of phenomena related to fate of chemicals in WWTP. / Enligt kemikalielagstiftningen REACH måste kemikalier som produceras i eller importeras till Europeiska unionen riskbedömas avseende hälso- och miljöfara. Den ökande mängden kemikalier som används i samhället kräver snabbare och billigare alternativa riskbedömningsmetoder, såsom kvantitativa struktur-aktivitets- eller egenskapssamband (QSARs eller QSPRs). QSARs och QSPRs är datamodeller där samband söks korrelationer mellan data för kemikaliers struktur-relaterade egenskaper och t.ex. kemikaliers persistens eller (eko)toxiska effekter. Målet med den här avhandlingen var att utvärdera och utveckla modeller för riskbedömning av industri kemikalier och läkemedel för att studera hur QSARs/QSPRs kan förbättra riskbedömningsprocessen. Fokus i avhandlingen var utveckling av metoder för identifiering av potentiellt cancerframkallande (C), mutagena (M), eller reproduktionstoxiska (R) kemikalier, och endokrint aktiva kemikalier, att studera betydelsen av metabolism vid riskbedömning och att öka vår förståelse för joniserbara kemikaliers adsorption till avloppsslam. Avhandlingen behandlar även konsensusmodellering, beskrivning av modellers giltighet och betydelsen av jonisering för kemiska deskriptorer. De huvudsakliga resultaten som presenteras i avhandlingen är: QSAR-modeller identifierade nästan alla cancerframkallande ämnen och de flesta mutagener men var sämre på att identifiera reproduktionstoxiska kemikalier. Metabolisk aktivering är av stor betydelse vid identifikationen av potentiellt toxiska kemikalier, speciellt för kemikalier som påvisar östrogen- (E) och sköldkörtel-relaterade (T) förändringar av det endokrina systemet men även för mutagener. Träffsäkerheten för de tillgängliga metabolismsimulatorerna är ganska låg för industriella kemikalier men i kombination med QSARs så var verktyget användbart för identifikation av kemikalier som påvisade E- och T-relaterade effekter in vivo. Vi rekommenderar att använda konsensusmodellering vid in silico baserad bedömning av kemikaliers toxicitet, d.v.s. att skapa en sammanvägd förutsägelse baserat på flera QSAR-modeller. Det är speciellt användbart för modeller som baseras på data från delvis olika mekanismer eller arter. QSAR-modeller måste ha ett väldefinierat giltighetsområde (AD) för att garantera dess pålitlighet vilket kan uppnås med t.ex. conformal prediction (CP)-metoden. CP-metoden ger en bättre kontroll över prediktiva gränser hos QSAR-modeller än andra distansbaserade AD-metoder. Läkemedel kan interagera med avloppsslam genom olika intermolekylära krafter som även påverkas av joniseringstillståndet. Modellerna visade att adsorptionen av neutrala och positivt laddade läkemedel var huvudsakligen hydrofobicitetsdrivna men också påverkade av Pi-Pi- och dipol-dipol-krafter. Negativt laddade molekyler interagerade huvudsakligen med slam via kovalent bindning och jon-jon-, jon-dipol-, och dipol-dipol-krafter. Kemiska deskriptorer baserade på joniserade molekyler förbättrade inte prestandan för adsorptionsmodeller för positiva och negativa joner men vi noterade en förbättring av modeller för neutrala substanser som kan bero på en mer korrekt beskrivning av zwitterjoner. Sammanfattningsvis visade resultaten på QSAR-modellers styrkor och svagheter för användning som verkyg vid risk- och exponeringsbedömning av kemikalier. QSARs har stor potential för bred användning vid riskidentifiering och för att förutsäga en mängd olika responser som krävs vid riskbedömning av kemikalier. I kombination med andra verktyg kan QSARs förse oss med data för användning vid integrerade bedömningar där data sammanvägs från olika metoder. De erhållna resultaten visar också att QSARs kan användas för att bedöma och ge en bättre förståelse för kemikaliers öde i vattenreningsverk.

Les polychlorobiphényles (PCB) et notamment les congénères les plus présents dans les sites et sols pollués, les PCB non dioxin like, constituent un danger sanitaire potentiel. Le risque associé est exacerbé chez le jeune enfant (6 mois à 3 ans) du fait, notamment, de son comportement exploratoire qui, de plus, a lieu durant une période critique de la croissance. L'objectif principal de cette thèse a été de caractériser l'impact des caractéristiques du sol sur la biodisponibilité relative des PCB. Les résultats in vivo ont montré l'impact des caractéristiques de la matière organique des sols sur la biodisponibilité relative des PCB par l'emploi de sols artificiels. Plusieurs matières organiques standardisées ont été testées allant des matières organiques solubles (acides fulviques, acides humiques) à une matière organique à la condensation maximale : le charbon actif. Ces éléments ont permis de montrer de larges variations de biodisponibilité relative allant d'une biodisponibilité relative nulle (charbon actif) à 100% (acide fulvique). Ces données soulignent l'importance de la condensation de la matière organique dans la rétention des PCB durant les processus digestifs. L'impact de caractéristiques (contenu en carbone organique, argile, black carbon, pH, concentrations en PCB) de sols historiquement contaminés sur la biodisponibilité a ensuite été évalué. Le taux de carbone organique et en black carbon sur la rétention des PCB. Toutefois la biodisponibilité relative demeure supérieure à 45% quel que soit le sol étudié. Les PCB sont donc peu retenus par le sol. Ainsi, l'exposition aux PCB via l'ingestion de sol semble proportionnelle à la quantité ingérée / Polychlorobiphenyls (PCBs) and, overall, non-dioxin-like PCBs (NDL-PCBs) the most abundant congeners in contaminated environmental matrices, constitute a potential health hazard. This risk is even more acute for young children (6 month to 3-year-old) because of their mouthing activities and because this exposure occurs during a critical part of their growth. The main objective of this thesis was to characterise the impact of soil's characteristics on the relative bioavailability of PCBs. The impact of the soil organic matter characteristics on the relative bioavailability of PCBs was assessed using artificial soils. Several standardised organic matters were tested ranging from soluble organic matters (fulvic acids, humic acids) to one organic matters highly condensed, activated carbon, a model of black carbon. These elements lead to show important variations in terms of relative bioavailability from 0% (activated carbon) to 100%, maximal relative bioavailability (fulvic acids). These findings highlight the importance of OM condensation in terms of PCB retention during the digestive processes. Then, the Impact of organic carbon, black carbon and clay content, pH, NDL-PCBs concentrations in historically contaminated soils on bioavailability and bioaccessibility was assessed. These approaches tended to show the importance of OC and BC content on retention of PCBs. Relative bioavailability was found to be higher than 45%, whatever the soil. Thus, PCBs retention in contaminated soils appears rather limited. Finally, exposure to PCBs via soil ingestion appears proportional to the quantity ingested

Relationships between occupational physical exposures and risks of contracting musculoskeletal disorders are still not well understood; exposure-response relationships are scarce in the musculoskeletal epidemiology literature, and many epidemiological studies, including intervention studies, fail to reach conclusive results. Insufficient exposure assessment has been pointed out as a possible explanation for this deficiency. One important aspect of assessing exposure is the selected measurement strategy; this includes issues related to the necessary number of data required to give sufficient information, and to allocation of measurement efforts, both over time and between subjects in order to achieve precise and accurate exposure estimates. These issues have been discussed mainly in the occupational hygiene literature considering chemical exposures, while the corresponding literature on biomechanical exposure is sparse. The overall aim of the present thesis was to increase knowledge on the relationship between data collection design and the resulting precision and accuracy of biomechanical exposure assessments, represented in this thesis by upper arm postures during work, data which have been shown to be relevant to disorder risk. Four papers are included in the thesis. In papers I and II, non-parametric bootstrapping was used to investigate the statistical efficiency of different strategies for distributing upper arm elevation measurements between and within working days into different numbers of measurement periods of differing durations. Paper I compared the different measurement strategies with respect to the eventual precision of estimated mean exposure level. The results showed that it was more efficient to use a higher number of shorter measurement periods spread across a working day than to use a smaller number for longer uninterrupted measurement periods, in particular if the total sample covered only a small part of the working day. Paper II evaluated sampling strategies for the purpose of determining posture variance components with respect to the accuracy and precision of the eventual variance component estimators. The paper showed that variance component estimators may be both biased and imprecise when based on sampling from small parts of working days, and that errors were larger with continuous sampling periods. The results suggest that larger posture samples than are conventionally used in ergonomics research and practice may be needed to achieve trustworthy estimates of variance components. Papers III and IV focused on method development. Paper III examined procedures for estimating statistical power when testing for a group difference in postures assessed by observation. Power determination was based either on a traditional analytical power analysis or on parametric bootstrapping, both of which accounted for methodological variance introduced by the observers to the exposure data. The study showed that repeated observations of the same video recordings may be an efficient way of increasing the power in an observation-based study, and that observations can be distributed between several observers without loss in power, provided that all observers contribute data to both of the compared groups, and that the statistical analysis model acknowledges observer variability. Paper IV discussed calibration of an inferior exposure assessment method against a superior “golden standard” method, with a particular emphasis on calibration of observed posture data against postures determined by inclinometry. The paper developed equations for bias correction of results obtained using the inferior instrument through calibration, as well as for determining the additional uncertainty of the eventual exposure value introduced through calibration. In conclusion, the results of the present thesis emphasize the importance of carefully selecting a measurement strategy on the basis of statistically well informed decisions. It is common in the literature that postural exposure is assessed from one continuous measurement collected over only a small part of a working day. In paper I, this was shown to be highly inefficient compared to spreading out the corresponding sample time across the entire working day, and the inefficiency was also obvious when assessing variance components, as shown in paper II. The thesis also shows how a well thought-out strategy for observation-based exposure assessment can reduce the effects of measurement error, both for random methodological variance (paper III) and systematic observation errors (bias) (paper IV).

First Nations peoples experience many benefits from eating locally-harvested wild foods, but these benefits must be considered along with the potential risks associated with exposure to environmental contaminants. Unlike store-bought foods, wild foods are an important traditional resource and a significant source of dietary protein, essential minerals and polyunsaturated fatty acids, believed to help in the prevention and treatment of obesity and obesity-related diseases such as type-2 diabetes mellitus. Wild foods continue to be an important and healthy food choice for First Nations peoples; however, they are also a primary source of dietary mercury, polychlorinated biphenyls (PCBs) and other persistent organic pollutants (POPs). To assess the effects of wild food consumption on dietary markers and contaminant accumulation, we grouped individuals from two remote Oji-Cree First Nations communities of north-western Ontario (n=71) according to their level of wild food consumption. In this study, I observed significantly higher organic contaminants in blood and higher mercury concentrations in hair for individuals consuming greater amounts of wild food. Age-adjusted contaminant concentrations were on average 3.5-times higher among high-frequency wild food consumers, with many exceeding federal and international health guidelines for mercury and PCB exposures. Contaminants in these populations approach, and in some cases exceed, threshold levels for adverse effects with potential consequences especially for prenatal development. Here, I also investigated the potential for stable isotope ratios of carbon and nitrogen (δ13C and δ15N) to serve as dietary markers and found strong positive correlations between stable isotopes and frequency of wild food and fish consumption. Frequency of fish consumption and δ15N was also shown to be positively correlated with mercury concentrations in hair and PCB concentrations in plasma. The results of this thesis demonstrate that known differences in dietary behaviour are clearly reflected in stable isotope ratios and contaminant concentrations. The data also show that contaminant exposures to those consuming wild foods in remote Boreal ecosystems is comparable to those associated with serious health effects in industrialized areas, and the problem of contaminants in wild foods is more widespread than the available literature would have led us to believe. These results affect our appreciation of contaminant exposures to First Nations peoples and will have implications for dietary choices, particularly if individuals are encouraged to consume greater amounts of wild foods for their proposed health benefits. We recommend further attention be given to the risks of contaminants in locally-harvested wild foods when promoting the benefits of their consumption to First Nations people as the problem of contaminants in remote communities practicing traditional lifestyles is often underreported and underplayed.