An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components-notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.

a b s t r a c tInhaled aerosol dose models play critical roles in medicine, the regulation of air pollutants and basic research. The models fall into several categories: traditional, computational fluid dynamical (CFD), physiologically based pharmacokinetic (PBPK), empirical, semi-empirical, and "reference". Each type of model has its strengths and weaknesses, so multiple models are commonly used for practical applications. Aerosol dose models combine information on aerosol behavior and the anatomy and physiology of exposed human and laboratory animal subjects. Similar models are used for in-vitro studies. Several notable advances have been made in aerosol dose modeling in the past 80 years. The pioneers include Walter Findeisen, who in 1935 published the first traditional model and established the structure of modern models. His model combined aerosol behavior with simplified respiratory tract structures. Ewald Weibel established morphometric techniques for the lung in 1963 that are still used to develop data for modeling today. Advances in scanning techniques have similarly contributed to the knowledge of respiratory tract structure and its use in aerosol dose modeling. Several scientists and research groups have developed and advanced traditional, CFD, and PBPK models. Current issues under study include understanding individual and species differences; examining localized particle deposition; modeling non-ideal aerosols and nanoparticle behavior; linking the regions of the respiratory tract airways from nasal-oral to alveolar; and developing sophisticated supporting software. Although a complete history of inhaled aerosol dose modeling is far too extensive to cover here, selected highlights are described in this paper.

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Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes. Owing to its ability to excise thymine when mispaired with guanine, it was proposed to act against the mutability of 5-methylcytosine (5-mC) deamination in mammalian DNA. However, TDG was also found to interact with transcription factors, histone acetyltransferases and de novo DNA methyltransferases, and it has been associated with DNA demethylation in gene promoters following activation of transcription, altogether implicating an engagement in gene regulation rather than DNA repair. Here we use a mouse genetic approach to determine the biological function of this multifaceted DNA repair enzyme. We find that, unlike other DNA glycosylases, TDG is essential for embryonic development, and that this phenotype is associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg null embryos (mouse embryonic fibroblasts, MEFs) show impaired gene regulation, coincident with imbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells (ESCs), but epigenetic aberrations only appear upon cell lineage commitment. We show that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant de novo methylation. We thus conclude that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage committed cells.