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Konig A.,University of Oxford | Konig A.,University of Luxembourg | Kuiper H.A.,Wageningen University | Marvin H.J.P.,Wageningen University | And 19 more authors.
Food Control | Year: 2010

Three main changes to current risk analysis processes are proposed to improve their transparency, openness, and accountability. First, the addition of a formal framing stage would allow interested parties, experts and officials to work together as needed to gain an initial shared understanding of the issue, the objectives of regulatory action, and alternative risk management measures. Second, the scope of the risk assessment is expanded to include the assessment of health and environmental benefits as well as risks, and the explicit consideration of economic- and social-impacts of risk management action and their distribution. Moreover approaches were developed for deriving improved information from genomic, proteomic and metabolomic profiling methods and for probabilistic modelling of health impacts for risk assessment purposes. Third, in an added evaluation stage, interested parties, experts, and officials may compare and weigh the risks, costs, and benefits and their distribution. As part of a set of recommendations on risk communication, we propose that reports on each stage should be made public. © 2010 Elsevier Ltd.

Agne B.,University of Neuchatel | Andres C.,University of Neuchatel | Montandon C.,University of Neuchatel | Christ B.,University of Zurich | And 6 more authors.
Plant Physiology | Year: 2010

The translocon at the outer membrane of the chloroplast assists the import of a large class of preproteins with amino-terminal transit sequences. The preprotein receptors Toc159 and Toc33 in Arabidopsis (Arabidopsis thaliana) are specific for the accumulation of abundant photosynthetic proteins. The receptors are homologous GTPases known to be regulated by phosphorylation within their GTP-binding domains. In addition to the central GTP-binding domain, Toc159 has an acidic N-terminal domain (A-domain) and a C-terminal membrane-anchoring domain (M-domain). The A-domain of Toc159 is dispensable for its in vivo activity in Arabidopsis and prone to degradation in pea (Pisum sativum). Therefore, it has been suggested to have a regulatory function. Here, we show that in Arabidopsis, the A-domain is not simply degraded but that it accumulates as a soluble, phosphorylated protein separated from Toc159. However, the physiological relevance of this process is unclear. The data show that the A-domain of Toc159 as well as those of its homologs Toc132 and Toc120 are targets of a casein kinase 2-like activity. © 2010 American Society of Plant Biologists.

Lo Sasso G.,Philip Morris International Research and Development | Titz B.,Philip Morris International Research and Development | Nury C.,Philip Morris International Research and Development | Boue S.,Philip Morris International Research and Development | And 18 more authors.
Inhalation Toxicology | Year: 2016

The liver is one of the most important organs involved in elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains more than 7000 chemicals, including those that exert biological effects and cause smoking-related diseases. Though CS is not directly hepatotoxic, a growing body of evidence suggests that it may exacerbate pre-existing chronic liver disease. In this study, we integrated toxicological endpoints with molecular measurements and computational analyses to investigate effects of exposures on the livers of Apoe−/− mice. Mice were exposed to 3R4F reference CS, to an aerosol from the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product (MRTP) or to filtered air (Sham) for up to 8 months. THS2.2 takes advantage of a “heat-not-burn” technology that, by heating tobacco, avoids pyrogenesis and pyrosynthesis. After CS exposure for 2 months, some groups were either switched to the MRTP or filtered air. While no group showed clear signs of hepatotoxicity, integrative analysis of proteomics and transcriptomics data showed a CS-dependent impairment of specific biological networks. These networks included lipid and xenobiotic metabolism and iron homeostasis that likely contributed synergistically to exacerbating oxidative stress. In contrast, most proteomic and transcriptomic changes were lower in mice exposed to THS2.2 and in the cessation and switching groups compared to the CS group. Our findings elucidate the complex biological responses of the liver to CS exposure. Furthermore, they provide evidence that THS2.2 aerosol has reduced biological effects, as compared with CS, on the livers of Apoe−/− mice. © 2016 Taylor & Francis.

Weitkunat R.,Philip Morris International Research and Development | Lee P.N.,P.N. Lee Statistics and Computing Ltd. | Baker G.,Philip Morris International Research and Development | Sponsiello-Wang Z.,Philip Morris International Research and Development | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2015

Based on the Food and Drug Administration's Modified Risk Tobacco Product (MRTP) Application draft guideline, Philip Morris International (PMI) has developed a Population Health Impact Model to estimate the reduction in the number of deaths over a period following the introduction of an MRTP. Such a model is necessary to assess the effect that its introduction would have on population health, given the lack of epidemiological data available prior to marketing authorization on any risks from MRTPs. The model is based on publicly available data on smoking prevalence and on the relationships between smoking-related disease-specific mortality and various aspects of the smoking of conventional cigarettes (CCs), together with an estimate of exposure from the MRTP relative to that from CCs, and allows the exploration of possible scenarios regarding the effect of MRTP introduction on the prevalence of CC and MRTP use, individually and in combination. By comparing mortality attributable in a scenario where the MRTP is introduced with one where it is not, the model can estimate the mortality attributable to CCs and the MRTP, as well as the reduction in the deaths attributable to the introduction of the MRTP. © 2015 The Authors.

Winkelmann C.,Philip Morris International Research and Development | Winkelmann C.,Philip Morris Products S.A. | Nordlund M.,Philip Morris International Research and Development | Nordlund M.,Philip Morris Products S.A. | And 5 more authors.
International Journal for Numerical Methods in Fluids | Year: 2014

The dynamics of a single-species aerosol composed of droplets in air is described in terms of nucleation, evaporation, condensation, and coagulation processes. We present a comprehensive overview of the Euler-Euler formulation, which gives rise to a model in which fast nucleation that initiates aerosol droplets co-exists with comparably slow condensation. The latter process is responsible for the subsequent growth of the droplets. To accurately represent the dynamical consequences of the fast nucleation process, while retaining numerical efficiency, a new second-order time-integration method for the nucleation, evaporation, and condensation processes is proposed and analyzed. The new time-integration method takes the form of a 'corrected Euler forward' method. It includes rapid nucleation bursts and their possible cessation within a time step Δt. If the current nucleation burst persists for longer than the next time step, it is included fully, whereas cessation of the nucleation burst within the next Δt implies corrections to the effective rates in the algorithm. The identification of these two situations corresponds to the physical mechanism by which nucleation of a supersaturated vapor is halted because of the progressing condensation onto the already formed droplets. The resulting time-integration method is shown to be second-order accurate in time, whereas the computational costs per time step were found to be increased by less than 25% compared with the Euler forward method. The new method is also applied in combination with advective transport of the aerosol forming vapor to investigate a front of rapid nucleation. Adopting robust first-order upwinding for the spatial discretization, we arrive at a flexible method that shows an overall first-order convergence in Δt. For the full, spatially dependent system motivated by an aerosol of water droplets in air, the computational benefits of the new time-integration method over the Euler forward scheme, are a factor of about 10 improvements in accuracy at a given Δt and a similar factor in computing time when keeping the same level of accuracy. © 2013 John Wiley & Sons, Ltd.

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