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Ann F Hubbs - One of the best experts on this subject based on the ideXlab platform.
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inhalation dosimetry of Diacetyl and butyric acid two components of butter flavoring vapors
Toxicological Sciences, 2009Co-Authors: John B Morris, Ann F HubbsAbstract:Occupational exposure to butter flavoring vapors (BFV) is associated with significant pulmonary injury. The goal of the current study was to characterize inhalation dosimetric patterns of Diacetyl and butyric acid, two components of BFV, and to develop a hybrid computational fluid dynamic-physiologically based pharmacokinetic model (CFD-PBPK) to describe these patterns. Uptake of Diacetyl and butyric acid vapors, alone and in combination, was measured in the upper respiratory tract of anesthetized male Sprague-Dawley rats under constant velocity flow conditions and the uptake data were used to validate the CFD-PBPK model. Diacetyl vapor (100 or 300 ppm) was scrubbed from the airstream with 76-36% efficiency at flows of 100-400 ml/min. Butryic acid (30 ppm) was scrubbed with >90% efficiency. Concurrent exposure to butyric acid resulted in a small but significant reduction of Diacetyl uptake (36 vs. 31%, p < 0.05). Diacetyl was metabolized in nasal tissues in vitro, likely by Diacetyl reductase, an enzyme known to be inhibited by butyric acid. The CFD-PBPK model closely described Diacetyl uptake; the reduction in Diacetyl uptake by butyric acid could be explained by inhibition of Diacetyl reductase. Extrapolation to the human via the model suggested that inspired Diacetyl may penetrate to the intrapulmonary airways to a greater degree in the human than in the rat. Thus, based on dosimetric relationships, extrapulmonary airway injury in the rat may be predictive of intrapulmonary airway injury in humans. Butyric acid may modulate Diacetyl toxicity by inhibiting its metabolism and/or altering its inhalation dosimetric patterns.
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respiratory toxicologic pathology of inhaled Diacetyl in sprague dawley rats
Toxicologic Pathology, 2008Co-Authors: Ann F Hubbs, W T Goldsmith, Michael L Kashon, David G Frazer, Robert R Mercer, Lori A Battelli, Gregory J Kullman, Diane Schweglerberry, Sherri Friend, Vincent CastranovaAbstract:Inhalation of butter flavoring vapors by food manufacturing workers causes an emerging lung disease clinically resembling bronchiolitis obliterans. Diacetyl, an α-diketone, is a major component of these vapors. In rats, we investigated the toxicity of inhaled Diacetyl at concentrations of up to 365 ppm (time weighted average), either as six-hour continuous exposures or as four brief, intense exposures over six hours. A separate group inhaled a single pulse of ~1800 ppm Diacetyl (92.9 ppm six-hour average). Rats were necropsied 18 to 20 hours after exposure. Diacetyl inhalation caused epithelial necrosis and suppurative to fibrinosuppurative inflammation in the nose, larynx, trachea, and bronchi. Bronchi were affected at Diacetyl concentrations of 294.6 ppm or greater; the trachea and larynx were affected at Diacetyl concentrations of 224 ppm or greater. Both pulsed and continuous exposure patterns caused epithelial injury. The nose had the greatest sensitivity to Diacetyl. Ultrastructural changes in the t...
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popcorn worker s lung in vitro exposure to Diacetyl an ingredient in microwave popcorn butter flavoring increases reactivity to methacholine
Toxicology and Applied Pharmacology, 2006Co-Authors: J S Fedan, J Dowdy, K B Fedan, Ann F HubbsAbstract:Workers who inhale microwave popcorn butter flavorings experience decrements in lung function and can develop clinical bronchiolitis obliterans, i.e., “popcorn worker's lung” (Kreiss, K., Gomaa, A., Kullman, G., Fedan, K., Simoes, E.J., Enright, P.L., 2002. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N. Engl. J. Med. 347, 330–338). In a rat inhalation model, vapors of an artificial butter flavoring damaged the epithelium of the upper and lower airways (Hubbs, A.F., Battelli, L.A., Goldsmith, W.T., Porter, D.W., Frazer, D., Friend, S., Schwegler-Berry, D., Mercer, R.R., Reynolds, J.S., Grote, A., Castranova, V., Kullman, G., Fedan, J.S., Dowdy, J., Jones, W.G., 2002. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol. Appl. Pharmacol. 185, 128–135). Diacetyl, a butter flavoring component, is a major volatile ketone in the popcorn-processing workplace. We investigated the effects of Diacetyl on epithelium of guinea pig isolated airway preparations and the effects of Diacetyl in vitro on reactivity to bronchoactive agents. In the isolated, perfused trachea preparation, Diacetyl added to the intraluminal (mucosal) bath elicited responses that began with contraction (threshold ca. 3 mM) and ended with relaxation. After a 4-h incubation with intraluminal Diacetyl (3 mM), contractions to extraluminal (serosal) methacholine (MCh) were slightly increased; however, sensitivity to intraluminally (mucosally) applied MCh was increased by 10-fold. Relaxation responses of MCh (3 × 10 −7 M)contracted tracheas to extraluminally applied terbutaline and intraluminally applied 120 mM KCl, to evoke epithelium-derived relaxing factor release, were unaffected by Diacetyl. Exposure of the tracheal epithelium in Ussing chambers to Diacetyl decreased transepithelial potential difference and resistance. These findings suggest that Diacetyl exposure compromised epithelial barrier function, leading to hyperreactivity to mucosally applied MCh. The respiratory epithelium appears to serve as an initial target for the toxic effects of Diacetyl in the airways. Published by Elsevier Inc.
John B Morris - One of the best experts on this subject based on the ideXlab platform.
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a validated hybrid computational fluid dynamics physiologically based pharmacokinetic model for respiratory tract vapor absorption in the human and rat and its application to inhalation dosimetry of Diacetyl
Toxicological Sciences, 2011Co-Authors: Eric Gloede, Joshua B Baldino, Joseph A Cichocki, John B MorrisAbstract:Diacetyl vapor is associated with bronchiolar injury in man but primarily large airway injury in the rat. The goal of this study was to develop a physiologically based pharmacokinetic model for inspired vapor dosimetry and to apply the model to Diacetyl. The respiratory tract was modeled as a series of airways: nose, trachea, main bronchi, large bronchi, small bronchi, bronchioles, and alveoli with tissue dimensions obtained from the literature. Airborne vapor was allowed to absorb (or desorb) from tissues based on mass transfer coefficients. Transfer of vapor within tissues was based on molecular diffusivity with direct reaction with tissue substrates and/or metabolism being allowed in each tissue compartment. In vitro studies were performed to provide measures of Diacetyl metabolism kinetics and direct reaction rates allowing for the development of a model with no unassigned variables. Respiratory tract uptake of halothane, acetone, ethanol and Diacetyl was measured in male F344 rat to obtain data for model validation. The human model was validated against published values for inspired vapor uptake. For both the human and rat models, a close concordance of model estimates with experimental measurements was observed, validating the model. The model estimates that limited amounts of inspired Diacetyl penetrate to the bronchioles of the rat (<2%), whereas in the lightly exercising human, 24% penetration to the bronchioles is estimated. Bronchiolar tissue concentrations of Diacetyl in the human are estimated to exceed those in the rat by 40-fold. These inhalation dosimetric differences may contribute to the human-rat differences in Diacetyl-induced airway injury.
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inhalation dosimetry of Diacetyl and butyric acid two components of butter flavoring vapors
Toxicological Sciences, 2009Co-Authors: John B Morris, Ann F HubbsAbstract:Occupational exposure to butter flavoring vapors (BFV) is associated with significant pulmonary injury. The goal of the current study was to characterize inhalation dosimetric patterns of Diacetyl and butyric acid, two components of BFV, and to develop a hybrid computational fluid dynamic-physiologically based pharmacokinetic model (CFD-PBPK) to describe these patterns. Uptake of Diacetyl and butyric acid vapors, alone and in combination, was measured in the upper respiratory tract of anesthetized male Sprague-Dawley rats under constant velocity flow conditions and the uptake data were used to validate the CFD-PBPK model. Diacetyl vapor (100 or 300 ppm) was scrubbed from the airstream with 76-36% efficiency at flows of 100-400 ml/min. Butryic acid (30 ppm) was scrubbed with >90% efficiency. Concurrent exposure to butyric acid resulted in a small but significant reduction of Diacetyl uptake (36 vs. 31%, p < 0.05). Diacetyl was metabolized in nasal tissues in vitro, likely by Diacetyl reductase, an enzyme known to be inhibited by butyric acid. The CFD-PBPK model closely described Diacetyl uptake; the reduction in Diacetyl uptake by butyric acid could be explained by inhibition of Diacetyl reductase. Extrapolation to the human via the model suggested that inspired Diacetyl may penetrate to the intrapulmonary airways to a greater degree in the human than in the rat. Thus, based on dosimetric relationships, extrapulmonary airway injury in the rat may be predictive of intrapulmonary airway injury in humans. Butyric acid may modulate Diacetyl toxicity by inhibiting its metabolism and/or altering its inhalation dosimetric patterns.
Brian Gibson - One of the best experts on this subject based on the ideXlab platform.
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125th Anniversary Review: Diacetyl and its control during brewery fermentation
Journal of The Institute of Brewing, 2013Co-Authors: Kristoffer Krogerus, Brian GibsonAbstract:Diacetyl is a butter-tasting vicinal diketone produced as a by-product of yeast valine metabolism during fermentation. Concentration is dependent on a number of factors including rate of formation of the precursor α-acetolactate by yeast, spontaneous decarboxylation of this acetohydroxy acid to Diacetyl and removal of Diacetyl by yeast via the action of various reductase enzymes. Lowering concentrations of Diacetyl in green beer represents an expensive and time-consuming part of the brewing process and strategies to minimize Diacetyl formation or hasten its reduction have potential for improving overall efficiency of the lager brewing system. Here we review the processes that determine Diacetyl levels in green beer as well as the various ways in which Diacetyl levels can be controlled. The amount of Diacetyl produced during fermentation can be affected by modifying process conditions, wort composition or fermentation technique, or by yeast strain development through genetic engineering or adaptive evolution. The process of Diacetyl reduction by yeast is not as well understood as the process of formation, but is dependent on factors such as physiological condition, cell membrane composition, temperature and pH. The process of Diacetyl removal is typically rate-limited by the reaction rate for the spontaneous decarboxylation of α-acetolactate to Diacetyl. Copyright © 2013 The Institute of Brewing & Distilling
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influence of valine and other amino acids on total Diacetyl and 2 3 pentanedione levels during fermentation of brewer s wort
Applied Microbiology and Biotechnology, 2013Co-Authors: Kristoffer Krogerus, Brian GibsonAbstract:Undesirable butter-tasting vicinal diketones are produced as by-products of valine and isoleucine biosynthesis during wort fermentation. One promising method of decreasing Diacetyl production is through control of wort valine content since valine is involved in feedback inhibition of enzymes controlling the formation of Diacetyl precursors. Here, the influence of valine supplementation, wort amino acid profile and free amino nitrogen content on Diacetyl formation during wort fermentation with the lager yeast Saccharomyces pastorianus was investigated. Valine supplementation (100 to 300 mg L−1) resulted in decreased maximum Diacetyl concentrations (up to 37 % lower) and Diacetyl concentrations at the end of fermentation (up to 33 % lower) in all trials. Composition of the amino acid spectrum of the wort also had an impact on Diacetyl and 2,3-pentanedione production during fermentation. No direct correlation between the wort amino acid concentrations and Diacetyl production was found, but rather a negative correlation between the uptake rate of valine (and also other branched-chain amino acids) and Diacetyl production. Fermentation performance and yeast growth were unaffected by supplementations. Amino acid addition had a minor effect on higher alcohol and ester composition, suggesting that high levels of supplementation could affect the flavour profile of the beer. Modifying amino acid profile of wort, especially with respect to valine and the other branched-chain amino acids, may be an effective way of decreasing the amount of Diacetyl formed during fermentation.
Ralf Kölling - One of the best experts on this subject based on the ideXlab platform.
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Diacetyl Formation by Oenococcus oeni during Winemaking Induced by Exogenous Pyruvate
American Journal of Enology and Viticulture, 2014Co-Authors: Roman Mink, Stephan Sommer, Ralf Kölling, Hans-georg Schmarr, Maren Scharfenberger-schmeerAbstract:Pyruvate is the central metabolite in Diacetyl synthesis by Oenococcus oeni. Therefore, any substrate that increases intracellular pyruvate concentration can induce Diacetyl accumulation. This study evaluates the effect of exogenous pyruvate on Diacetyl formation and the expression of Diacetyl-related genes in Oenococcus oeni during winemaking. Diacetyl formation by Oenococcus oeni was induced by yeast-derived pyruvate in the early stage of winemaking. Furthermore, when additional pyruvate was added, α-acetolactate synthase ( alsS ) gene expression increased 1.6-fold and the Diacetyl concentration increased from 0.4 mg/L to 2.3 mg/L. Although the highest alsS expression (a 10-fold increase) was found 24 hr after pyruvate addition, no further increase in Diacetyl concentration was found. In addition, alsD was overexpressed (9-fold) at that point, indicating that α-acetolactate was converted into acetoin. Together, the results show that exogenous pyruvate induces Diacetyl formation by Oenococcus oeni in the early stage of winemaking . Furthermore, pyruvate-derived Diacetyl accumulates because of a delayed alsD response that prevents acetoin formation.
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Diacetyl reduction by commercial Saccharomyces cerevisiae strains during vinification
Journal of the Institute of Brewing, 2013Co-Authors: Roman Mink, Stephan Sommer, Ralf Kölling, Hans-georg Schmarr, Louis Baumbach, Maren Scharfenberger-schmeerAbstract:Microbially derived Diacetyl accumulation during vinification imparts a buttery wine aroma, which has stylistic implications. However, at higher concentrations Diacetyl induces an aromatic off-flavour. Saccharomyces cerevisiae is able to reduce Diacetyl to below the sensory threshold. Therefore, characterization of the Diacetyl reduction in commercial wine yeasts creates new opportunities to manage the risk of wine associated off-flavours. Diacetyl reduction by two commercial S. cerevisiae strains was characterized in Pinot blanc grape must of the vintage 2012 with different initial Diacetyl concentrations (0–50 mg/L). Highest Diacetyl reduction was found in the first two days after wine yeasts were inoculated. No further decrease in Diacetyl content was observed after the fourth day. All assays in which Diacetyl was added showed the same final Diacetyl concentration of approximately 2 mg/L. However, a significantly lower amount of Diacetyl was found in grape must without adding Diacetyl. The present results indicate that commercial wine yeasts are able to reduce much higher amounts of Diacetyl than normally expected during the vinification procedure. However, the constant final Diacetyl concentration indicates that Diacetyl accumulation may be the result of wine matrix binding effects, which prevent a complete reduction by active wine yeasts. Copyright © 2013 The Institute of Brewing & Distilling.
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cytosolic localization of acetohydroxyacid synthase ilv2 and its impact on Diacetyl formation during beer fermentation
Applied and Environmental Microbiology, 2011Co-Authors: Suvarna Dasari, Ralf KöllingAbstract:Diacetyl (2,3-butanedione) imparts an unpleasant "butterscotch-like" flavor to alcoholic beverages such as beer, and therefore its concentration needs to be reduced below the sensory threshold before packaging. We examined the mechanisms that lead to highly elevated Diacetyl formation in petite mutants of Saccharomyces cerevisiae during beer fermentations. We present evidence that elevated Diacetyl formation is tightly connected to the mitochondrial import of acetohydroxyacid synthase (Ilv2), the key enzyme in the production of Diacetyl. Our data suggest that accumulation of the matrix-targeted Ilv2 preprotein in the cytosol is responsible for the observed high Diacetyl levels. We could show that the Ilv2 preprotein accumulates in the cytosol of petite yeasts. Furthermore, expression of an Ilv2 variant that lacks the N-terminal mitochondrial targeting sequence and thus cannot be imported into mitochondria led to highly elevated Diacetyl levels comparable to a petite strain. We further show that expression of a mutant allele of the γ-subunit of the F(1)-ATPase (ATP3-5) could be an attractive way to reduce Diacetyl formation by petite strains.
Kristoffer Krogerus - One of the best experts on this subject based on the ideXlab platform.
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125th Anniversary Review: Diacetyl and its control during brewery fermentation
Journal of The Institute of Brewing, 2013Co-Authors: Kristoffer Krogerus, Brian GibsonAbstract:Diacetyl is a butter-tasting vicinal diketone produced as a by-product of yeast valine metabolism during fermentation. Concentration is dependent on a number of factors including rate of formation of the precursor α-acetolactate by yeast, spontaneous decarboxylation of this acetohydroxy acid to Diacetyl and removal of Diacetyl by yeast via the action of various reductase enzymes. Lowering concentrations of Diacetyl in green beer represents an expensive and time-consuming part of the brewing process and strategies to minimize Diacetyl formation or hasten its reduction have potential for improving overall efficiency of the lager brewing system. Here we review the processes that determine Diacetyl levels in green beer as well as the various ways in which Diacetyl levels can be controlled. The amount of Diacetyl produced during fermentation can be affected by modifying process conditions, wort composition or fermentation technique, or by yeast strain development through genetic engineering or adaptive evolution. The process of Diacetyl reduction by yeast is not as well understood as the process of formation, but is dependent on factors such as physiological condition, cell membrane composition, temperature and pH. The process of Diacetyl removal is typically rate-limited by the reaction rate for the spontaneous decarboxylation of α-acetolactate to Diacetyl. Copyright © 2013 The Institute of Brewing & Distilling
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influence of valine and other amino acids on total Diacetyl and 2 3 pentanedione levels during fermentation of brewer s wort
Applied Microbiology and Biotechnology, 2013Co-Authors: Kristoffer Krogerus, Brian GibsonAbstract:Undesirable butter-tasting vicinal diketones are produced as by-products of valine and isoleucine biosynthesis during wort fermentation. One promising method of decreasing Diacetyl production is through control of wort valine content since valine is involved in feedback inhibition of enzymes controlling the formation of Diacetyl precursors. Here, the influence of valine supplementation, wort amino acid profile and free amino nitrogen content on Diacetyl formation during wort fermentation with the lager yeast Saccharomyces pastorianus was investigated. Valine supplementation (100 to 300 mg L−1) resulted in decreased maximum Diacetyl concentrations (up to 37 % lower) and Diacetyl concentrations at the end of fermentation (up to 33 % lower) in all trials. Composition of the amino acid spectrum of the wort also had an impact on Diacetyl and 2,3-pentanedione production during fermentation. No direct correlation between the wort amino acid concentrations and Diacetyl production was found, but rather a negative correlation between the uptake rate of valine (and also other branched-chain amino acids) and Diacetyl production. Fermentation performance and yeast growth were unaffected by supplementations. Amino acid addition had a minor effect on higher alcohol and ester composition, suggesting that high levels of supplementation could affect the flavour profile of the beer. Modifying amino acid profile of wort, especially with respect to valine and the other branched-chain amino acids, may be an effective way of decreasing the amount of Diacetyl formed during fermentation.