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Problems for which it is impossible to make a precise causal prediction are commonly tackled with statistical analysis. Although fairly simple, the problem of a rocking block on a rigid base subjected to seismic excitation exhibits a fascinating, complex response, making it extremely difficult to validate numerical models against experimental results, thus calling for a statistical approach. In this context, this paper statistically studies the rocking behaviour of rigid blocks, excited by synthetic far-field ground motions. A total of 50 million analyses are performed, considering rocking blocks of height ranging from 1 to 20 m and slenderness angle ranging from 0.1 to 0.35 rad. The results are used to explore the performance of different ground motion intensity measures (IMs), in terms of their ability to predict the maximum rocking rotation. By comparing the efficiency, sufficiency and proficiency of the IMs, it is found that the peak ground velocity (PGV) performs optimally. Then, fragility curves are constructed using different IMs, concluding again that the PGV is the most efficient IM. Impressively, the fragility curves for different block sizes collapse to a single curve, if a non-dimensional IM that involves PGV and the block geometry is used. Finally, the results produced on the basis of far-field synthetic motions are compared to results based on recorded ground motions., Earthquake Engineering & Structural Dynamics, 51 (15), ISSN:0098-8847, ISSN:1096-9845

The simplest 3D extension of Housner's planar rocking model is a rocking (wobbling) cylinder allowed to uplift and roll on its circumference, but constrained not to roll out of its initial position. The model is useful for the description of bridges that use rocking as a seismic isolation technique, in an effort to save material by reducing the design moment and the size of the foundations. This paper shows that describing wobbling motion in terms of displacements rather than rotations is more useful. It unveils that a remarkable property of planar rocking bodies extends to 3D motion: A small and a large wobbling cylinder of the same slenderness will sustain roughly equal top displacement, as long as they are not close to overturning. This allows for using the response of an infinitely large wobbling cylinder of slenderness alpha as a proxy to compute the response of all cylinders having the same slenderness, irrespectively of their size. Thus, the dimensionality of the problem is reduced by one. Moreover, this paper shows that the median wobbling response to sets of ground motions can be described as an approximate function of only two non-dimensional parameters, namely (gtan alpha/PGA,u/PGD)or (gtan alpha/PGA,uPGA/PGV2) where u is the top displacement of the wobbling body., Earthquake Engineering & Structural Dynamics, 51 (2), ISSN:0098-8847, ISSN:1096-9845

Scope: Furan, a food contaminant formed during heat processing, induces hepatocellular tumors in rodents and high incidences of cholangiocarcinomas in rats even at the lowest dose (2 mg/kg b.w.) administered. Initial estimates suggested that human intake of furan may be as high as 3.5 μg/kg b.w./day, indicating a relatively narrow margin of exposure. The aim of this study was to establish dose–response data for cytotoxicity, regenerative cell proliferation and secondary oxidative DNA damage in livers of male F344 rats treated with furan at doses ≤2 mg/kg b.w. for 28 days. Methods and results: No significant signs of hepatotoxicity other than a mild, dose-dependent increase in serum cholesterol and unconjugated bile acids, and no evidence of oxidative DNA damage were seen. Histopathological alterations and proliferative changes were restricted to subcapsular areas of the left and caudate liver lobes. Conclusion: Although statistically significant effects were only seen at the 2 mg/kg b.w. dose during the course of our study, a ∼two and ∼threefold increase in 5-bromo-2′-deoxyuridine labeling index was observed at 0.1 and 0.5 mg/kg b.w., respectively, suggesting that chronic exposure to doses even below 2 mg/kg b.w. may cause proliferative changes in rat liver and highlighting the need to assess furan carcinogenicity at lower doses.

The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling (" omics" ) technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyzed in relation to routine clinical chemistry and histopathology. Four of the sixteen hepato- and/or nephrotoxicants given to rats for 1, 3, or 14. days at two dose levels induced similar histopathological effects. These were characterized by bile duct necrosis and hyperplasia and/or increased bilirubin and cholestasis, in addition to hepatocyte necrosis and regeneration, hepatocyte hypertrophy, and hepatic inflammation. Combined analysis of liver transcriptomics data from these studies revealed common gene expression changes which allowed the development of a potential sequence of events on a mechanistic level in accordance with classical endpoint observations. This included genes implicated in early stress responses, regenerative processes, inflammation with inflammatory cell immigration, fibrotic processes, and cholestasis encompassing deregulation of certain membrane transporters. Furthermore, a preliminary classification analysis using transcriptomics data suggested that prediction of cholestasis may be possible based on gene expression changes seen at earlier time-points. Targeted bile acid analysis, based on LC-MS metabonomics data demonstrating increased levels of conjugated or unconjugated bile acids in response to individual compounds, did not provide earlier detection of toxicity as compared to conventional parameters, but may allow distinction of different types of hepatobiliary toxicity. Overall, liver transcriptomics data delivered mechanistic and molecular details in addition to the classical endpoint observations which were further enhanced by targeted bile acid analysis using LC/MS metabonomics. © 2010 Elsevier Inc.

Although early detection of toxicant induced kidney injury during drug development and chemical safety testing is still limited by the lack of sensitive and reliable biomarkers of nephrotoxicity, omics technologies have brought enormous opportunities for improved detection of toxicity and biomarker discovery. Thus, transcription profiling has led to the identification of several candidate kidney biomarkers such as kidney injury molecule (Kim-1), clusterin, lipocalin-2, and tissue inhibitor of metalloproteinase 1 (Timp-1), and metabonomic analysis of urine is increasingly used to indicate biochemical perturbations due to renal toxicity. This study was designed to assess the value of a combined (1)H-NMR and gas chromatography-mass spectrometry (GC-MS) metabonomics approach and a set of novel urinary protein markers for early detection of nephrotoxicity following treatment of male Wistar rats with gentamicin (60 and 120 mg/kg bw, s.c.) for 7 days. Time- and dose-dependent separation of gentamicin-treated animals from controls was observed by principal component analysis of (1)H-NMR and GC-MS data. The major metabolic alterations responsible for group separation were linked to the gut microflora, thus related to the pharmacology of the drug, and increased glucose in urine of gentamicin-treated animals, consistent with damage to the S(1) and S(2) proximal tubules, the primary sites for glucose reabsorption. Altered excretion of urinary protein biomarkers Kim-1 and lipocalin-2, but not Timp-1 and clusterin, was detected before marked changes in clinical chemistry parameters were evident. The early increase in urine, which correlated with enhanced gene and protein expression at the site of injury, provides further support for lipocalin-2 and Kim-1 as sensitive, noninvasive biomarkers of nephrotoxicity.