Human variability in influx and efflux transporters in relation to uncertainty factors for chemical risk assessment

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Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment

Human variability in paraoxonase-1 (PON1) activities is driven by genetic polymorphisms that affect the internal dose of active oxons of organophosphorus (OP) insecticides. Here, an extensive literature search has been performed to collect human genotypic frequencies (i.e. L55M, Q192R, and C-108T) in subgroups from a range of geographical ancestry and PON1 activities in three probe substrates (paraoxon, diazoxon and phenyl acetate). Bayesian meta-analyses were performed to estimate variability distributions for PON1 activities and PON1-related uncertainty factors (UFs), while integrating quantifiable sources of inter-study, inter-phenotypic and inter-individual differences. Inter-phenotypic differences were quantified using the population with high PON1 activity as the reference group. Results from the meta-analyses provided PON1 variability distributions and these can be implemented in generic physiologically based kinetic models to develop quantitative in vitro in vivo extrapolation models. PON1-related UFs in the Caucasian population were above the default toxicokinetic UF of 3.16 for two specific genotypes namely −108CC using diazoxon as probe substrate and, −108CT, −108TT, 55MM and 192QQ using paraoxon as probe substrate. However, integration of PON1 genotypic frequencies and activity distributions showed that all UFs were within the default toxicokinetic UF. Quantitative inter-individual differences in PON1 activity are important for chemical risk assessment particularly with regards to the potential sensitivity to organophosphates' toxicity. Keywords: Human variability, PON1 activity, Polymorphism, Uncertainty facto

Inherited liver shunts in dogs elucidate pathways regulating embryonic development and clinical disorders of the portal vein

Congenital disorders of the hepatic portal vasculature are rare in man but occur frequently in certain dog breeds. In dogs, there are two main subtypes: intrahepatic portosystemic shunts, which are considered to stem from defective closure of the embryonic ductus venosus, and extrahepatic shunts, which connect the splanchnic vascular system with the vena cava or vena azygos. Both subtypes result in nearly complete bypass of the liver by the portal blood flow. In both subtypes the development of the smaller branches of the portal vein tree in the liver is impaired and terminal branches delivering portal blood to the liver lobules are often lacking. The clinical signs are due to poor liver growth, development, and function. Patency of the ductus venosus seems to be a digenic trait in Irish wolfhounds, whereas Cairn terriers with extrahepatic portosystemic shunts display a more complex inheritance. The genes involved in these disorders cannot be identified with the sporadic human cases, but in dogs, the genome-wide study of the extrahepatic form is at an advanced stage. The canine disease may lead to the identification of novel genes and pathways cooperating in growth and development of the hepatic portal vein tree. The same pathways likely regulate the development of the vascular system of regenerating livers during liver diseases such as hepatitis and cirrhosis. Therefore, the identification of these molecular pathways may provide a basis for future proregenerative intervention

Towards a systematic method for assessing the impact of chemical pollution on ecosystem services of water systems

Contains fulltext : 231437.pdf (publisher's version ) (Open Access

Integrating hydrology and geophysics into a traditional geology field course: The use of advanced project options

The incorporation of increasingly multidisciplinary aspects of geoscience curricula into a traditional geology field camp requires compromises. Among these, decisions about projects to reduce or eliminate and course prerequisites are two of the most challenging. Over the past 10 years, the University of Missouri's geology field camp has completed a two-stage plan to expand our projects in hydrology and geophysics while maintaining traditional aspects of our course and our standard prerequisites

Seasonal variation in cascade-driven hyporheic exchange, northern Honduras

A characterization of hyporheic exchange for dry and wet season baseflow, as well as partially dewatered discharge, was done in Prieta Creek, a first-order cascade in northern Honduras. The cascade had discharges from 1 to 15 l s-1, had average slopes of 12%, pool spacing of 3 m, and shallow substrate of sand and gravel. Tracer tests were conducted in a 15-m sub-reach, a length considered to be adequate for the experiment based on the DaI test, a ratio of exchange and transport processes. In the three tests, between 9 and 18% of tracer was not recovered, possibly due to entrainment in flowpaths passing beneath the downstream monitoring location. Tracer data were analysed by the one-dimensional transport with inflow and storage (OTIS) transient storage model (TSM) to derive standard exchange parameters, and by the solute transport in rivers (STIR) model to examine hyporheic residence time distributions (RTDs). The best fit of the observed tracer breakthrough curves was obtained by using the STIR model with a combination of two exponential RTDs to represent hyporheic retention. With increasing discharge, the OTIS model predicted increasing storage exchange fluxes and exchange coefficients and decreasing storage zone areas and transient storage times, which are trends supported by riparian and streambed piezometric head data. Riparian water levels rose during the transition from the dry to wet season, which could constrict the hyporheic storage zone. Thirteen of the 19 streambed piezometers recorded seasonal changes in hydraulic gradients and flux direction, with fewer yet stronger upwelling zones during higher discharges. The MODFLOW model missed the observed seasonal changes, possibly due to subtle changes in the seasonal change in water surface profiles. We conclude that partially dewatered dry season exchange, compared to wet season exchange, was initiated and terminated with smaller pressure gradients and, in different streambed locations, was smaller in volume, had longer residence times, and may connect with deeper and longer flow paths. © 2010 John Wiley & Sons, Ltd

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro–in vivo extrapolations in chemical risk assessment are discussed

Determination of alkyl chain tilt angles in Langmuir monolayers: A comparison of Brewster angle autocorrelation spectroscopy and x-ray diffraction

Brewster angle autocorrelation spectroscopy (BAAS), a combination of Brewster angle microscopy and the photocorrelation technique is a new method for the quantitative characterization of Langmuir monolayers. In this paper we compare tilt angle measurements in octadecanol monolayers performed using BAAS and grazing incidence x-ray diffraction (GIXD). BAAS offers the possibility of tilt angle measurements in Langmuir monolayers—without any fitted parameters—with a precision similar to GIXD, but ten times faster. GIXD, conversely, offers detailed microscopic information not available from BAAS. The swiftness of BAAS is exploited for a detailed analysis of the phase transitions from the L′2L2′ phase to the LSLS (Rotator I) and LSLS (Rotator II) phases. The L′2/LSL2′/LS (Rot I) transition is of first order whereas the L′2/LSL2′/LS (Rot II) transition is more probably of weak first order than of second order