Mode of action-based risk assessment of genotoxic carcinogens

The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as “omics” approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B$_{1}$, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs

The Potential for Augmented Reality to Bring Balance betweenthe Ease of Pedestrian Navigation and the Acquisition of Spatial Knowledge

Being completely lost in an unfamiliar environment can be inconvenient, stressful and, at times, even dangerous. Maps are the traditional tools used for guidance but many people find maps difficult to use. In recent years, new tools like outdoor Augmented Reality (AR) have become available which allow virtual navigation cues to be directly overlaid on the real world, potentially overcoming the limitations of maps. However, it has been hypothesized that lower effort invested in processing navigation guidance may lead to diminished spatial knowledge (SK) thereby making users of such navigation tools far more vulnerable to getting lost should the tools fail for any reason. This thesis explores the research question of how AR and maps compare as tools for pedestrian navigation guidance as well as for SK acquisition and if there is a potential for AR tools be developed that would balance the two. We present a series of studies to better understand the consequences of using AR in a pedestrian navigation tool. The first two studies compared time-on-task performance and user preferences for AR and Map navigation interfaces on an outdoor navigation task. The results were not aligned with expectations, which led us to build a controlled testing environment for comparing AR and map navigation. Using this simulated setting, our third study verified the assumption that AR can indeed result in more efficient navigation performance and it supported the hypothesis that this would come at the cost of weaker SK. In our fourth study, we used a dual task design to compare the relative cognitive resources required by map and AR interfaces. The quantitative data collected indicated that users could potentially accept additional workload designed to improve SK without incurring significantly more effort. Our fifth and final study explored an interface with additional AR cues that could potentially balance navigation guidance with SK acquisition. The contributions of this thesis include insights into performance issues relating to AR, a classification of user types based on navigation tool usage behavior, a testbed for simulating perfect AR tracking in a virtual setting, objective measures for determining route knowledge, the capacity that pedestrian navigation tool users may have for performing additional tasks, and guidelines that would be helpful in the design of pedestrian navigation tools