Effects of the popcorn flavorings, diacetyl and 2,3-pentanedione, in the airways

Popcorn workers\u27 lung (PWL) is a bronchiolitis obliterans-like obstructive disease caused by inhalation of butter flavoring vapor during the manufacture of microwave popcorn. Lung function tests of employees at several microwave popcorn plants revealed that the severity of abnormal lung function correlated with increasing cumulative exposure to the butter flavorant, diacetyl. Recently, the diacetyl substitute, 2,3-pentanedione, has also been identified as a respiratory hazard. The National Institute for Occupational Safety and Health (NIOSH) demonstrated in rats that inhalation of occupationally-relevant concentrations of diacetyl and 2,3-pentanedione vapor for 6 h resulted in airway epithelial necrosis and apoptosis in the nasal passages 18 h after exposure. Anatomical differences in the airways exist between animals and humans, which, in turn, give rise to different sites of lung injury after flavoring exposure. However, a consistent feature from these studies is the demonstration that the airway epithelium is a major target of injury after flavoring exposure.;Our hypothesis was, diacetyl and 2,3-pentanedione damage airway epithelium by altering epithelial ion transport and tight junction integrity, and modifying airway smooth muscle (ASM), contributing to initial pathophysiological events leading to flavoring-induced lung disease. The focus of the first specific aim was to investigate concentration-response relationships for flavoring induced toxicity in rats, assessing changes in respiratory mechanics and reactivity to methacholine (MCh). There was negligible change in vivo in basal lung resistance (RL) and basal dynamic compliance (C dyn) 18 h after a 6-h inhalation exposure to diacetyl or 2,3-pentanedione (100--360 ppm). Despite evidence of substantial epithelial damage in upper airways of the rat, reactivity to MCh was not increased after flavoring exposure but was slightly decreased. Other flavorings, such as acetic acid and acetoin, are often present in abundant amounts in butter flavoring vapor (Boylstein et al., 2006; van Rooy et al., 2007, 2009). Reactivity to MCh was also slightly decreased in mixed flavoring exposures diacetyl (250 ppm) + acetoin (150 ppm) + acetic acid (27 ppm). In order to evaluate epithelium function and integrity as well as effects on ASM, the rat isolated, perfused trachea preparation (IPT) was employed. Diacetyl exposure caused essentially no effect on reactivity to mucosally-applied MCh 18 h after 6 h exposure; in contrast, 2,3-pentanedione (320 and 360 ppm) increased reactivity to MCh. To further investigate the effects of flavoring on ASM, we assessed diacetyl and 2,3-pentanedione (≥3 mM) applied to the serosal and mucosal surfaces of intact and denuded tracheas in IPT, which resulted in ASM relaxation independent of the presence of epithelium. The purpose of the second specific aim was to investigate the potential mechanisms of this flavoring-induced relaxation. Using precontracted rat tracheal strips (MCh; 3x10 -5 M), we investigated the potential involvement of bitter taste receptors (TAS2Rs) in denatonium (1 mM) and flavoring-induced relaxant responses of ASM and bioelectric responses of tracheal epithelial cells. For the first time, it was demonstrated that the TAS2R agonist, denatonium, induces ASM relaxation in rat tracheal strips via an iberiotoxin-dependant pathway. Flavoring-induced relaxation and reduced short-circuit current (ISC) were not mediated by TAS2R. The purpose of the third specific aim was to understand better the bioelectric responses caused by diacetyl and 2,3-pentanedione vapor on the airway epithelium and to determine toxic flavoring concentrations. Malfunctions of pulmonary epithelial ion transport processes and, therefore, impairment of the liquid balance in the airways is associated with severe respiratory diseases, such as cystic fibrosis and pulmonary edema. Normal human bronchial/tracheal epithelial cells (NHBEs) were exposed to flavoring vapor using a custom-made apparatus and then assessed for changes in ion transport. Concentrations at 60 ppm and above resulted in cell death. Ussing chamber studies indicated that 6 h of flavoring exposure at 25 ppm significantly reduced amiloride (3.5x10-5 M)-sensitive Na + transport but not NPPB (10-4 M)-sensitive Cl - transport at a 0 h post-exposure time point. Thus, our results indicated that flavoring-induced loss of apical Na+ conductance. These studies helped to clarify the direct effects of the flavorings on the epithelium as well as potentially identifying their initial pathophysiological effects. In addition, we demonstrated that NHBEs metabolize diacetyl and 2,3-pentanedione vapors during exposure.;This dissertation begins with an overall literature review in Chapter 1, with the primary focus on inhalation exposure to diacetyl and 2,3-pentanedione vapor, resulting in PWL. Chapters 2, 3, and 4, focus on each Specific Aim, our results, and the comparison of diacetyl and 2,3-pentanedione as well as possible underlying mechanisms of toxicity. Chapter 5 is an extension of Chapter 4 and describes an emerging study of diacetyl and 2,3-pentanedione metabolism by epithelial cells. Finally, the general discussion is found in Chapter 6. (Abstract shortened by UMI.)

Approximate analytical description of the nonaffine response of amorphous solids

An approximation scheme for model disordered solids is proposed that leads to the fully analytical evaluation of the elastic constants under explicit account of the inhomogeneity (nonaffinity) of the atomic displacements. The theory is in quantitative agreement with simulations for central-force systems and predicts the vanishing of the shear modulus at the isostatic point with the linear law {\mu} ~ (z - 2d), where z is the coordination number. The vanishing of rigidity at the isostatic point is shown to be a consequence of the canceling out of positive affine and negative nonaffine terms

Local structure controls shear and bulk moduli in disordered solids

This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep18724Paradigmatic model systems, which are used to study the mechanical response of matter, are random networks of point-atoms, random sphere packings, or simple crystal lattices; all of these models assume central-force interactions between particles/atoms. Each of these models differs in the spatial arrangement and the correlations among particles. In turn, this is reflected in the widely different behaviours of the shear (G) and compression (K) elastic moduli. The relation between the macroscopic elasticity as encoded in G, K and their ratio, and the microscopic lattice structure/order, is not understood. We provide a quantitative analytical connection between the local orientational order and the elasticity in model amorphous solids with different internal microstructure, focusing on the two opposite limits of packings (strong excluded-volume) and networks (no excluded-volume). The theory predicts that, in packings, the local orientational order due to excluded-volume causes less nonaffinity (less softness or larger stiffness) under compression than under shear. This leads to lower values of G/K, a well-documented phenomenon which was lacking a microscopic explanation. The theory also provides an excellent one-parameter description of the elasticity of compressed emulsions in comparison with experimental data over a broad range of packing fractions.This work was supported by the Theoretical Condensed Matter programme grant from EPSRC. M.S. thanks the Konrad-Adenauer-Stiftung for their financial support

Quantifying the Reversible Association of Thermosensitive Nanoparticles

Under many conditions, biomolecules and nanoparticles associate by means of attractive bonds, due to hydrophobic attraction. Extracting the microscopic association or dissociation rates from experimental data is complicated by the dissociation events and by the sensitivity of the binding force to temperature (T). Here we introduce a theoretical model that combined with light-scattering experiments allows us to quantify these rates and the reversible binding energy as a function of T. We apply this method to the reversible aggregation of thermoresponsive polystyrene/poly(N-isopropylacrylamide) core-shell nanoparticles, as a model system for biomolecules. We find that the binding energy changes sharply with T, and relate this remarkable switchable behavior to the hydrophobic-hydrophilic transition of the thermosensitive nanoparticles

Shear-induced reaction-limited aggregation kinetics of Brownian particles at arbitrary concentrations

The aggregation of interacting Brownian particles in sheared concentrated suspensions is an important issue in colloid and soft matter science per se. Also, it serves as a model to understand biochemical reactions occurring in vivo where both crowding and shear play an important role. We present an effective medium approach within the Smoluchowski equation with shear which allows one to calculate the encounter kinetics through a potential barrier under shear at arbitrary colloid concentrations. Experiments on a model colloidal system in simple shear flow support the validity of the model in the range considered. By generalizing Kramers' rate theory to the presence of collective hydrodynamics, our model explains the significant increase in the shear-induced reaction-limited aggregation kinetics upon increasing the colloid concentration

Atomic theory of viscoelastic response and memory effects in metallic glasses

An atomic-scale theory of the viscoelastic response of metallic glasses is derived from first principles, using a Zwanzig-Caldeira-Leggett system-bath Hamiltonian as a starting point within the framework of nonaffine linear response to mechanical deformation. This approach provides a generalized Langevin equation (GLE) as the average equation of motion for an atom or ion in the material, from which non-Markovian nonaffine viscoelastic moduli are extracted. These can be evaluated using the vibrational density of states (DOS) as input, where the boson peak plays a prominent role in the mechanics. To compare with experimental data for binary ZrCu alloys, a numerical DOS was obtained from simulations of this system, which also take electronic degrees of freedom into account via the embedded-atom method for the interatomic potential. It is shown that the viscoelastic α-relaxation, including the α-wing asymmetry in the loss modulus, can be very well described by the theory if the memory kernel (the non-Markovian friction) in the GLE is taken to be a stretched-exponential decaying function of time. This finding directly implies strong memory effects in the atomic-scale dynamics and suggests that the α-relaxation time is related to the characteristic time scale over which atoms retain memory of their previous collision history

Kramers rate theory of ionization and dissociation of bound states

Calculating the microscopic dissociation rate of a bound state, such as a classical diatomic molecule, has been difficult so far. The problem was that standard theories require an energy barrier over which the bound particle (or state) escapes into the preferred low-energy state. This is not the case when the long-range repulsion responsible for the barrier is either absent or screened (as in Cooper pairs, ionized plasma, or biomolecular complexes). We solve this classical problem by accounting for entropic memory at the microscopic level. The theory predicts dissociation rates for arbitrary potentials and is successfully tested on the example of plasma, where it yields an estimate of ionization in the core of Sun in excellent agreement with experiments. In biology, the new theory accounts for crowding in receptor-ligand kinetics and protein aggregation

Non-affine lattice dynamics of defective fcc crystals

The mechanical, thermal and vibrational properties of defective crystals are important in many different contexts, from metallurgy and solid-state physics to, more recently, soft matter and colloidal physics. Here we study two different models of disordered fcc crystal lattices, with randomly-removed bonds and with vacancies, respectively, within the framework of non-affine lattice dynamics. We find that both systems feature the same scaling of the shear modulus with the newly defined inversion-symmetry breaking (ISB) parameter, which shows that local inversion-symmetry breaking around defects is the universal root source of the non-affine softening of the shear modulus. This finding allows us to derive analytical relations for the non-affine (zero-frequency) shear modulus as a function of vacancy concentration in excellent agreement with numerical simulations. Nevertheless, due to the different microstructural disorder, the spatial fluctuations of the local ISB parameter are different in the vacancy and bond-depleted case. The vacancy fcc exhibits comparatively a more heterogenous microstructural disorder (due to the broader distribution of coordination number Z), which is reflected in a different scaling relation between boson peak frequency in the DOS and the average [Z with combining macron]. These differences are less important at low vacancy concentrations, where the numerical DOS of the vacancy fcc can be well described theoretically by coherent-potential approximation, developed here for the bond-depleted fcc lattice in 3d