Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans.

A physiologically based pharmacokinetic (PBPK) model was developed and applied to a metabolic series approach for the ethyl series (i.e., ethyl acetate, ethanol, acetaldehyde, and acetate). This approach bases toxicity information on dosimetry analyses for metabolically linked compounds using pharmacokinetic data for each compound and toxicity data for parent or individual compounds. In vivo pharmacokinetic studies of ethyl acetate and ethanol were conducted in rats following IV and inhalation exposure. Regardless of route, ethyl acetate was rapidly converted to ethanol. Blood concentrations of ethyl acetate and ethanol following both IV bolus and infusion suggested linear kinetics across blood concentrations from 0.1 to 10 mM ethyl acetate and 0.01-0.8 mM ethanol. Metabolic parameters were optimized and evaluated based on available pharmacokinetic data. The respiratory bioavailability of ethyl acetate and ethanol were estimated from closed chamber inhalation studies and measured ventilation rates. The resulting ethyl series model successfully reproduces blood ethyl acetate and ethanol kinetics following IV administration and inhalation exposure in rats, and blood ethanol kinetics following inhalation exposure to ethanol in humans. The extrapolated human model was used to derive human equivalent concentrations for the occupational setting of 257-2120 ppm ethyl acetate and 72-517 ppm ethyl acetate for continuous exposure, corresponding to rat LOAELs of 350 and 1500 ppm.

Unrecognized volatile and semi-volatile organic compounds from brake wear.

Motor vehicles are among the major sources of pollutants and greenhouse gases in urban areas and a transition to "zero emission vehicles" is underway worldwide. However, emissions associated with brake and tire wear will remain. We show here that previously unrecognized volatile and semi-volatile organic compounds, which have a similarity to biomass burning emissions are emitted during braking. These include greenhouse gases or, these classified as Hazardous Air Pollutants, as well as nitrogen-containing organics, nitrogen oxides and ammonia. The distribution and reactivity of these gaseous emissions are such that they can react in air to form ozone and other secondary pollutants with adverse health and climate consequences. Some of the compounds may prove to be unique markers of brake emissions. At higher temperatures, nucleation and growth of nanoparticles is also observed. Regions with high traffic, which are often disadvantaged communities, as well as commuters can be impacted by these emissions even after combustion-powered vehicles are phased out.

Meat intake in Britain in relation to other dietary components and to demographic and risk factor variables: analyses based on the National Diet and Nutrition Survey of 2000/2001.

BACKGROUND: Red and processed meat intakes have been positively associated with the risk of several major chronic diseases. Understanding population intakes is important when formulating dietary recommendations. The present study investigated the dispersion of intakes of red and processed meat and associations with dietary, socio-demographic and risk factors. METHODS: The present study comprised a secondary analysis of the British National Diet and Nutrition Survey 2000/1, including 7-day dietary records, from 766 male and 958 female respondents aged 19-64 years. Composite dishes were disaggregated into primary ingredients. Self-reported vegetarians (V) were grouped into one stratum and other respondents were stratified into five groups (F1-F5) according to energy-adjusted red plus processed meat (RPM) intake, to give six strata. 7-day RPM intakes were adjusted to estimate 'usual' habitual intakes, using ratios of between-person to total variance in daily intakes. RESULTS: Mean recorded intakes of red, processed, white and total meat were 48, 41, 40 and 129 g day(-1) , respectively, in males and 30, 22, 30 and 82 g day(-1) in females. Estimated habitual intakes of RPM standardised to sex-specific energy intakes across the six strata were: 12 (V), 56, 76, 90, 105 and 137 g day(-1) in males and 5 (V), 34, 46, 55, 65 and 88 g day(-1) in females. Lower RPM consumers tended to be of higher social class and educational level and to have more favourable levels of some risk factors. CONCLUSIONS: Mean intakes of red, processed and white meat were of similar magnitude. Habitual intakes of RPM showed wide dispersion with one-quarter of males < 55 g day(-1) and one-quarter of females < 27 g day(-1) . Lowering overall RPM consumption could be achieved by seeking greater reductions among current high consumers.

Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition.

Chlorpyrifos (CPF) is an organophosphorus insecticide, and neurotoxicity results from inhibition of acetylcholinesterase (AChE) by its metabolite, chlorpyrifos-oxon. Routine consumption of alcohol and tobacco modifies metabolic and physiological processes impacting the metabolism and pharmacokinetics of other xenobiotics, including pesticides. This study evaluated the influence of repeated ethanol and nicotine coexposure on in vivo CPF dosimetry and cholinesterase (ChE) response (ChE- includes AChE and/or butyrylcholinesterase (BuChE)). Hepatic microsomes were prepared from groups of naive, ethanol-only (1 g/kg/d, 7 d, po), and ethanol + nicotine (1 mg/kg/d 7 d, sc)-treated rats, and the in vitro metabolism of CPF was evaluated. For in vivo studies, rats were treated with saline or ethanol (1 g/kg/d, po) + nicotine (1 mg/kg/d, sc) in addition to CPF (1 or 5 mg/kg/d, po) for 7 d. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), in blood and urine and the plasma ChE and brain acetylcholinesterase (AChE) activities were measured in rats. There were differences in pharmacokinetics, with higher TCPy peak concentrations and increased blood TCPy AUC in ethanol + nicotine groups compared to CPF only (approximately 1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain AChE activities after ethanol + nicotine treatments showed significantly less inhibition following repeated 5 mg CPF/kg dosing compared to CPF only (96 ± 13 and 66 ± 7% of naive at 4 h post last CPF dosing, respectively). Although brain AChE activity was minimal inhibited for the 1-mg CPF/kg/d groups, the ethanol + nicotine pretreatment resulted in a similar trend (i.e., slightly less inhibition). No marked differences were observed in plasma ChE activities due to the alcohol + nicotine treatments. In vitro, CPF metabolism was not markedly affected by repeated ethanol or both ethanol + nicotine exposures. Compared with a previous study of nicotine and CPF exposure, there were no apparent additional exacerbating effects due to ethanol coexposure.

Salmonella SdiA recognizes N-acyl homoserine lactone signals from Pectobacterium carotovorum in vitro, but not in a bacterial soft rot.

Genomes of Salmonella enterica isolates, including those linked to outbreaks of produce-associated gastroenteritis, contain sdiA, which encodes a receptor of N-acyl homoserine lactones (AHL). AHL are the quorum-sensing signals used by bacteria to coordinately regulate gene expression within -their populations. Because S. enterica does not produce its own AHL, SdiA is hypothesized to function in the interspecies cross-talk with AHL-producing bacteria. Under laboratory conditions, S. enterica responded to AHL from phytobacteria by upregulating expression of srgE. AHL-dependent expression of srgE required a functional sdiA. Essentially, no sdiA-dependent resolution of the srgE recombinase-based (RIVET) reporter was observed inside a soft rot formed on a tomato by an AHL-producing strain of Pectobacterium carotovorum. The results of the control experiments suggest that sdiA is not expressed inside tomato, pepper, green onion, or carrot affected by the soft rot, and the lack of sdiA expression in planta prevents Salmonella spp. from responding to AHL. Despite its inability to detect and respond to AHL during colonization of soft rots, S. enterica reached higher final cell numbers inside a tomato soft rot compared with its growth in intact tomato fruit. The synergistic effect was the strongest under the conditions that are typical for the Florida fall/winter production season.

Atlantic water flow pathways revealed by lead contamination in Arctic basin sediments.

Contaminant lead in sediments underlying boundary currents in the Arctic Ocean provides an image of current organization and stability during the past 50 years. The sediment distributions of lead, stable lead isotope ratios, and lead-210 in the major Arctic Ocean basins reveal close coupling of the Eurasian Basin with the North Atlantic during the 20th century. They indicate that the Atlantic water boundary current in the Eurasian Basin has been a prominent pathway, that contaminant lead from the Laptev Sea supplies surface water in the transpolar drift, and that the Canadian and Eurasian basins have been historically decoupled.

Impact of food and predation on the snowshoe hare cycle.

Snowshoe hare populations in the boreal forests of North America go through 10-year cycles. Supplemental food and mammalian predator abundance were manipulated in a factorial design on 1-square-kilometer areas for 8 years in the Yukon. Two blocks of forest were fertilized to test for nutrient effects. Predator exclosure doubled and food addition tripled hare density during the cyclic peak and decline. Predator exclosure combined with food addition increased density 11-fold. Added nutrients increased plant growth but not hare density. Food and predation together had a more than additive effect, which suggests that a three-trophic-level interaction generates hare cycles.

Dating and context of three middle stone age sites with bone points in the Upper Semliki Valley, Zaire.

The extent to which the earliest anatomically modern humans in Africa exhibited behavioral and cognitive traits typical of Homo sapiens sapiens is controversial. In eastern Zaire, archaeological sites with bone points have yielded dates older than 89(-15)+22 thousand years ago by several techniques. These include electron spin resonance, thermoluminescence, optically stimulated luminescence, uranium series, and amino acid racemization. Faunal and stratigraphic data are consistent with this age.

Effect of dimethylamine on the gas phase sulfuric acid concentration measured by Chemical Ionization Mass Spectrometry.

Sulfuric acid is widely recognized as a very important substance driving atmospheric aerosol nucleation. Based on quantum chemical calculations it has been suggested that the quantitative detection of gas phase sulfuric acid (H2SO4) by use of Chemical Ionization Mass Spectrometry (CIMS) could be biased in the presence of gas phase amines such as dimethylamine (DMA). An experiment (CLOUD7 campaign) was set up at the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber to investigate the quantitative detection of H2SO4 in the presence of dimethylamine by CIMS at atmospherically relevant concentrations. For the first time in the CLOUD experiment, the monomer sulfuric acid concentration was measured by a CIMS and by two CI-APi-TOF (Chemical Ionization-Atmospheric Pressure interface-Time Of Flight) mass spectrometers. In addition, neutral sulfuric acid clusters were measured with the CI-APi-TOFs. The CLOUD7 measurements show that in the presence of dimethylamine (<5 to 70 pptv) the sulfuric acid monomer measured by the CIMS represents only a fraction of the total H2SO4, contained in the monomer and the clusters that is available for particle growth. Although it was found that the addition of dimethylamine dramatically changes the H2SO4 cluster distribution compared to binary (H2SO4-H2O) conditions, the CIMS detection efficiency does not seem to depend substantially on whether an individual H2SO4 monomer is clustered with a DMA molecule. The experimental observations are supported by numerical simulations based on A Self-contained Atmospheric chemistry coDe coupled with a molecular process model (Sulfuric Acid Water NUCleation) operated in the kinetic limit.

Estimating the time to extinction in an island population of song sparrows.

We estimated and modelled how uncertainties in stochastic population dynamics and biases in parameter estimates affect the accuracy of the projections of a small island population of song sparrows which was enumerated every spring for 24 years. The estimate of the density regulation in a theta-logistic model (theta = 1.09 suggests that the dynamics are nearly logistic, with specific growth rate r1 = 0.99 and carrying capacity K = 41.54. The song sparrow population was strongly influenced by demographic (sigma2(d) = 0.66) and environmental (sigma2(d) = 0.41) stochasticity. Bootstrap replicates of the different parameters revealed that the uncertainties in the estimates of the specific growth rate r1 and the density regulation theta were larger than the uncertainties in the environmental variance sigma2(e) and the carrying capacity K. We introduce the concept of the population prediction interval (PPI), which is a stochastic interval which includes the unknown population size with probability (1 - alpha). The width of the PPI increased rapidly with time because of uncertainties in the estimates of density regulation as well as demographic and environmental variance in the stochastic population dynamics. Accepting a 10% probability of extinction within 100 years, neglecting uncertainties in the parameters will lead to a 33% overestimation of the time it takes for the extinction barrier (population size X = 1) to be included into the PPI. This study shows that ignoring uncertainties in population dynamics produces a substantial underestimation of the extinction risk.

Immigration and the ephemerality of a natural population bottleneck: evidence from molecular markers.

Population bottlenecks are often invoked to explain low levels of genetic variation in natural populations, yet few studies have documented the direct genetic consequences of known bottlenecks in the wild. Empirical studies of natural population bottlenecks are therefore needed, because key assumptions of theoretical and laboratory studies of bottlenecks may not hold in the wild. Here we present microsatellite data from a severe bottleneck (95% mortality) in an insular population of song sparrows (Melospiza melodia). The major findings of our study are as follows: (i) The bottleneck reduced heterozygosity and allelic diversity nearly to neutral expectations, despite non-random survival of birds with respect to inbreeding and wing length. (ii) All measures of genetic diversity regained pre-bottleneck levels within two to three years of the crash. This rapid recovery was due to low levels of immigration. (iii) The rapid recovery occurred despite a coincident, strong increase in average inbreeding. These results show that immigration at levels that are hard to measure in most field studies can lead to qualitatively very different genetic outcomes from those expected from mutations only. We suggest that future theoretical and empirical work on bottlenecks and metapopulations should address the impact of immigration.

Induction of the rat hepatic microsomal mixed-function oxidases by two aza-arenes. A comparison with their non-heterocyclic analogues.

The ability of the aza-aromatic polycyclic aromatic hydrocarbons 10-azobenz(a)pyrene and benz(a)acridine to induce the rat hepatic microsomal mixed-function oxidases was compared to that of their non-heterocyclic analogues benz(a)pyrene and benz(a)anthracene respectively. All four hydrocarbons markedly increased the O-deethylations of ethoxyresorufin and ethoxycoumarin, the non-heterocyclic analogues being the more potent. A more modest increase was seen in the O-dealkylation of pentoxyresorufin. All four hydrocarbons induced proteins recognised by antibodies to cytochrome P-450IAI but no increase was seen when antibodies to cytochrome P-450IIB1 were employed. The metabolic activation of benz(a)pyrene and Glu-P-1 to mutagenic intermediates in the Ames test was enhanced by all pretreatments. It is concluded that the aza-aromatic polycyclic hydrocarbons, like their non-heterocyclic analogues, selectively induce the cytochrome P-450I family of proteins.

Mechanisms of nitric oxide release from nitrovasodilators in aqueous solution: reaction of the nitroprusside ion ([Fe(CN)5NO]2-) with L-ascorbic acid.

Nitric Oxide (NO) is a very diverse endogenous molecule and is responsible for a number of mammalian physiological activities. Sodium nitroprusside (SNP) is a long known hypotensive agent due to its ability to produce NO in situ. In this study, we have carried out a detailed investigation on the kinetics and mechanism of the decomposition of SNP by L-ascorbic acid to afford NO in aqueous medium. Spectrophotometric and electrochemical methods were employed in these studies. Experiments were performed under an argon atmosphere and reaction rates were strongly pH dependent and increases with pH. NO release increases up to about pH 7 after which it decreases at higher pHs. The two ionized forms of ascorbate present in aqueous solution reduce SNP in the order A2->>HA->>H2A (H2A=L-ascorbic acid) to release NO. The outer-sphere reduction of SNP by ascorbate involved three clear stages with NO being released in the last stage. Our kinetic results also show catalysis by group 1 alkali metal ions to increase down the group from Li+ to Cs+. A detail study presented here, strongly illustrate the possibility of the biological antioxidant, L-ascorbic acid, to play a vital role in the in situ metabolism of nitrosocompounds such as SNP to produce NO.

Finch numbers, owl predation and plant dispersal on Isla Daphne Major, Galápagos.

Populations of 4 geospizine finches were studied on Isla Daphne Major in April and December 1973. Finches were captured, banded, measured and released in both months, and censused in December. 1640±711 finches were estimated to be present in December, of which probably more than 1000 belonged to Geospiza fortis. G. fortis were 4 times more numerous than G. scandens. The overal density at this time was 27-54/ha. This is the first quantitative estimate of finch population sizes for a whole island in the Galápagos Archipelago. Some G. fuliginosa and magnirostris immigrated between study periods, but overall density remained nearly constant. There was no evidence of immigration of fortis and scandens. Survival rates of the two common species, fortis and scandens, from April to December were estimated, from banded birds, to be 86.9% and 91.3%. Up to 300 finches (fortis and scandens) disappeared between study periods. The amount of predation by owls (Asio flammeus), estimated from an analysis of 49 pellets, could account for more than 50% of the finch losses, but is likely to be less. The estimated loss due to predation was less than 10% of the populations in April.The discovery of the remains of house mice, Mus musculus, and black rats, Rattus rattus, in pellets indicates that owls hunt on one island (e.g. Santa Cruz or Baltra) and regurgitate on another (Daphne). Fruits of a Euphorb, Chamaesyce amplexicaulis (Hook. f.) Burch, that finches eat were found in two pellets that also contained finch remains. This suggests that seeds or fruits in the throat of a victim at the time of a kill may be transported unharmed inside an owl from one island to another. Indirect support to this suggestion is given by the results of flotation experiments with seeds and fruits of 22 species of plants. Most did not float, and are too heavy to be transported by normal winds. Many do not have hooks or sticky surfaces, and internal transport by birds (including owls) is therefore strongly suggested.

Thermal inactivation D- and z-values of Salmonella serotypes and listeria innocua in chicken patties, chicken tenders, franks, beef patties, and blended beef and turkey patties.

Commercially formulated meat products, including chicken patties, chicken tenders, franks, beef patties, and blended beef and turkey patties, were obtained from processors. Each product was inoculated with 7 to 8 logs of Salmonella (Senftenberg, Typhimurium, Heidelberg, Mission, Montevideo, and California) or Listeria innocua. The inoculated meat samples were heat treated at 55 to 70 degrees C. At each temperature, the decimal reduction time (D) was obtained by linear regression of survival curves. Values of D and the temperature difference required for the thermal inactivation curve to drop a logarithmic cycle (z) were determined for the Salmonella serotypes and L. innocua in each product. At 55 to 70 degrees C. for the five tested products, the D-values for the Salmonella serotypes and L. innocua were 26.97 to 0.25 min and 191.94 to 0.18 min, respectively, and their z-values were 7.60 to 9.83 degrees C and 4.86 to 8.67 degrees C, respectively. Significant differences were found for the D- and z-values among the five products. This study will better enable processors to determine the process lethality of pathogens in commercial meat products.

Contaminants in the Canadian Arctic: 5 years of progress in understanding sources, occurrence and pathways.

Recent studies of contaminants under the Canadian Northern Contaminants Program (NCP) have substantially enhanced our understanding of the pathways by which contaminants enter Canada's Arctic and move through terrestrial and marine ecosystems there. Building on a previous review (Barrie et al., Arctic contaminants: sources, occurrence and pathways. Sci Total Environ 1992:1-74), we highlight new knowledge developed under the NCP on the sources, occurrence and pathways of contaminants (organochlorines, Hg, Pb and Cd, PAHs, artificial radionuclides). Starting from the global scale, we examine emission histories and sources for selected contaminants focussing especially on the organochlorines. Physical and chemical properties, transport processes in the environment (e.g. winds, currents, partitioning), and models are then used to identify, understand and illustrate the connection between the contaminant sources in industrial and agricultural regions to the south and the eventual arrival of contaminants in remote regions of the Arctic. Within the Arctic, we examine how contaminants impinge on marine and terrestrial pathways and how they are subsequently either removed to sinks or remain where they can enter the biosphere. As a way to focus this synthesis on key concerns of northern residents, a number of special topics are examined including: a mass balance for HCH and toxaphene (CHBs) in the Arctic Ocean; a comparison of PCB sources within Canada's Arctic (Dew Line Sites) with PCBs imported through long-range transport; an evaluation of concerns posed by three priority metals--Hg, Pb and Cd; an evaluation of the risks from artificial radionuclides in the ocean; a review of what is known about new-generation pesticides that are replacing the organochlorines; and a comparison of natural vs. anthropogenic sources of PAH in the Arctic. The research and syntheses provide compelling evidence for close connectivity between the global emission of contaminants from industrial and agricultural activities and the Arctic. For semi-volatile compounds that partition strongly into cold water (e.g. HCH) we have seen an inevitable loading of Arctic aquatic reservoirs. Drastic HCH emission reductions have been rapidly followed by reduced atmospheric burdens with the result that the major reservoir and transport agent has become the ocean. In the Arctic, it will take decades for the upper ocean to clear itself of HCH. For compounds that partition strongly onto particles, and for which the soil reservoir is most important (e.g. PCBs), we have seen a delay in their arrival in the Arctic and some fractionation toward more volatile compounds (e.g. lower-chlorinated PCBs). Despite banning the production of PCB in the 1970s, and despite decreases of PCBs in environmental compartments in temperate regions, the Arctic presently shows little evidence of reduced PCB loadings. We anticipate a delay in PCB reductions in the Arctic and environmental lifetimes measured in decades. Although artificial radionuclides have caused great concern due to their direct disposal on Russian Shelves, they are found to pose little threat to Canadian waters and, indeed, much of the radionuclide inventory can be explained as remnant global fallout, which was sharply curtailed in the 1960s, and waste emissions released under license by the European reprocessing plants. Although Cd poses a human dietary concern both for terrestrial and marine mammals, we find little evidence that Cd in marine systems has been impacted by human activities. There is evidence of contaminant Pb in the Arctic, but loadings appear presently to be decreasing due to source controls (e.g. removal of Pb from gasoline) in Europe and North America. Of the metals, Hg provokes the greatest concern; loadings appear to be increasing in the Arctic due to global human activities, but such loadings are not evenly distributed nor are the pathways by which they enter and move within the Arctic well understood.

Seasonal changes in density and tissue distribution of Onchocerca cervicalis microfilariae in ponies and related changes in Culicoides variipennis populations in Louisiana.

Seasonal changes in density and spatial distribution of Onchocerca cervicalis microfilariae were studied in ventral-midline skin of 15 infected pony mares in southern Louisiana. Triple running mean analysis of data over a 13-mo period indicated that a distinct pattern exists in total microfilariae population density and in microfilariae occurrence in different levels of the dermis. Microfilariae density reaches peak levels in the spring followed by a 58% decrease in the summer, a 19% increase in the fall, and a decrease to the lowest numbers in the winter. Microfilariae were found in all levels of the skin during the spring, summer, and fall but were not found in the superficial layers of the dermis during the winter months. The population density of Culicoides variipennis, a demonstrated vector of O. cervicalis, appeared to have seasonal fluctuations similar to the changes in microfilarial density. Harmonic wave analysis of microfilariae density data in individual ponies showed that all individuals did not follow the population trend.

New insights on the role of sea ice in intercepting atmospheric pollutants using (129)I.

Measurements of (129)I carried out on sea ice samples collected in the central Arctic Ocean in 2007 revealed relatively high levels in the range of 100-1400×10(7) at L(-1) that are comparable to levels measured in the surface mixed layer of the ocean at the same time. The (129)I/(127)I ratio in sea ice is much greater than that in the underlying water, indicating that the (129)I inventory in sea ice cannot be supported by direct uptake from seawater or by iodine volatilization from proximal (nearby) oceanic regimes. Instead, it is proposed that most of the (129)I inventory in the sea ice is derived from direct atmospheric transport from European nuclear fuel reprocessing plants at Sellafield and Cap La Hague. This hypothesis is supported by back trajectory simulations indicating that volume elements of air originating in the Sellafield/La Hague regions would have been present at arctic sampling stations coincident with sampling collection.

Effect of ribavirin on junin virus infection in guinea pigs.

Junin virus (JUNV) is the aetiological agent of Argentine haemorrhagic fever. The pathogenesis of the infection is not well understood, no licensed vaccines exist and no specific antiviral therapy is available. Previous studies have demonstrated the ability of ribavirin to delay and reduce JUNV disease and virus burden in guinea pigs without preventing death. Based on available data, we performed three different studies to determine the efficacy of ribavirin against JUNV in the guinea pig model with a focus on survival. Different doses and treatment schedules of ribavirin were tested in a lethal model of JUNV infection. Our results show that prolonged treatment with high doses of ribavirin significantly reduces the mortality in guinea pigs infected with JUNV. These results may be useful in future experimental studies or clinical testing.