5

Modeling and Simulation of Small Particles

FROM ATOMISTIC SIMULATIONS TO HEALTH EFFECTS

Epidemiological studies, said Angela Violi of the University of Michigan, have demonstrated a correlation between exposure to an elevated concentration of particles and the development of fibrosis and asthma. A variety of studies has shown that smaller particles are able to penetrate and accumulate deep within the alveolar regions of the lung. Exposure is not limited, however, to the lungs, because research has shown that particles can translocate out of the lungs and circulate throughout the body, even crossing the blood-brain barrier and entering the brain.

According to data from the Environmental Protection Agency (EPA), most particulate matter (PM) in urban environments is carbonaceous (Figure 5-1), and most enters the urban atmosphere as part of diesel exhaust (EPA, 2010). Violi noted that particles from 1 to 50 nanometers in diameter represent about 1 percent of the particle mass emitted from a diesel engine, but from 35 to 97 percent of the number of particles. Current EPA particle emissions standards apply only to particles of 2.5 microns or larger, which will have no impact on the particles that are most worrisome. She added that exhaust particles are not pure carbon; they carry carcinogenic compounds such as benzopyrene and other polyaromatic hydrocarbons and thus can serve as effective delivery vehicles for dangerous compounds.

Carbon particles form during combustion, whether it is in an engine cylinder or in a candle flame. The process starts with fuel molecules that are not oxidized completely and instead react with one another to form precursor molecules, which in turn react with one another to form polyaromatic hydrocarbons over a timeframe of 10 milliseconds or so. These reactions continue, and by 50 milliseconds the molecules grow to a point that chains and agglomerates begin to form. It is this time period, when gas-phase carcinogenic species form, but before soot forms, that Violi is working to model, with the eventual goal of examining how nanoparticles interact with biological systems.

“The problem with this kind of process is the timescale,” she explained. While particle formation takes place on a millisecond timescale, other chemistry that may take place on the surface of a growing particle, such as intramolecular rearrangements, can happen on the nanosecond to microsecond timescale. Modeling across both timescales is challenging.

Molecular dynamics modeling works very well for fast events, but even the biggest computers can only handle nanosecond timeframes for the complex processes involved in combustion particle formation. Continuum modeling could span the necessary timescale, but at the expense of excluding most of the chemical details. Instead, Violi’s group developed a computational code that combines aspects of molecular dynamics with a kinetic Monte Carlo approach. The resulting stochastic code, which she named Atomistic Model for Particle Interception (AMPI), follows the growth of particle formation over a long timescale and large length scale and retains information on the chemical and physical properties of the system (Violi and Venkatnathan, 2006, Chung and Violi, 2007).

Using this model, Violi and her colleagues can follow particle formation as a function of fuel and have shown that particle morphology and chemical composition change dramatically even though the number of carbon atoms in the combustion products remains the same. The model, which can grow particles up to 20 nanometers in diameter, also reveals that molecular morphology affects particle morphology, which in turn affects how the particles agglomerate and whether they form block-like structures or more flaky structures.

Violi explained that AMPI can provide information not only on particle morphology, but also on hydrogen-to-carbon



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5 Modeling and Simulation of Small Particles FROM ATOMISTIC SIMULATIONS TO HEALTH EFFECTS species form, but before soot forms, that Violi is working to model, with the eventual goal of examining how nano- Epidemiological studies, said Angela Violi of the Univer- particles interact with biological systems. sity of Michigan, have demonstrated a correlation between “The problem with this kind of process is the time- exposure to an elevated concentration of particles and the scale,” she explained. While particle formation takes place development of fibrosis and asthma. A variety of studies has on a millisecond timescale, other chemistry that may take shown that smaller particles are able to penetrate and accu- place on the surface of a growing particle, such as intra- mulate deep within the alveolar regions of the lung. Exposure molecular rearrangements, can happen on the nanosecond is not limited, however, to the lungs, because research has to microsecond timescale. Modeling across both timescales shown that particles can translocate out of the lungs and is challenging. circulate throughout the body, even crossing the blood-brain Molecular dynamics modeling works very well for fast barrier and entering the brain. events, but even the biggest computers can only handle According to data from the Environmental Protection nanosecond timeframes for the complex processes involved Agency (EPA), most particulate matter (PM) in urban envi- in combustion particle formation. Continuum modeling ronments is carbonaceous (Figure 5-1), and most enters the could span the necessary timescale, but at the expense of urban atmosphere as part of diesel exhaust (EPA, 2010). Violi excluding most of the chemical details. Instead, Violi’s group noted that particles from 1 to 50 nanometers in diameter developed a computational code that combines aspects of represent about 1 percent of the particle mass emitted from molecular dynamics with a kinetic Monte Carlo approach. a diesel engine, but from 35 to 97 percent of the number of The resulting stochastic code, which she named Atomistic particles. Current EPA particle emissions standards apply Model for Particle Interception (AMPI), follows the growth only to particles of 2.5 microns or larger, which will have of particle formation over a long timescale and large length no impact on the particles that are most worrisome. She scale and retains information on the chemical and physical added that exhaust particles are not pure carbon; they carry properties of the system (Violi and Venkatnathan, 2006, carcinogenic compounds such as benzopyrene and other Chung and Violi, 2007). polyaromatic hydrocarbons and thus can serve as effective Using this model, Violi and her colleagues can follow delivery vehicles for dangerous compounds. particle formation as a function of fuel and have shown Carbon particles form during combustion, whether it is in that particle morphology and chemical composition change an engine cylinder or in a candle flame. The process starts dramatically even though the number of carbon atoms in the with fuel molecules that are not oxidized completely and combustion products remains the same. The model, which can instead react with one another to form precursor molecules, grow particles up to 20 nanometers in diameter, also reveals which in turn react with one another to form polyaromatic that molecular morphology affects particle morphology, which hydrocarbons over a timeframe of 10 milliseconds or so. in turn affects how the particles agglomerate and whether they These reactions continue, and by 50 milliseconds the mol- form block-like structures or more flaky structures. ecules grow to a point that chains and agglomerates begin Violi explained that AMPI can provide information not to form. It is this time period, when gas-phase carcinogenic only on particle morphology, but also on hydrogen-to-carbon 47

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48 CHALLENGES IN CHARACTERIZING SMALL PARTICLES FIGURE 5-1 Four-season average of PM2.5 composition for 15 U.S. cities, 2008. SOURCE: EPA, 2010. ratio, free radical concentration, surface reactivity, optical 5-1and through which diffusion can occur. Using a molecular new properties, functional group distribution, porosity, surface dynamics approach, Violi’s team has been able to model how area, pore size distribution, surface-averaged energy distribu- uneditable bitmaped carbonaceous particles of varying morphologies impact the tion, and particle density. “The whole point of this modeling natural diffusion of lipids that is constantly taking place in approach is that the transition from gas phase to particles is the cell membrane. Indeed, model calculations show that very fast, and there are very few techniques—I think almost carbonaceous nanoparticles immediately alter lipid diffu - none—that can deal with the 1-to-50-nanometers range,” she sion and that the alterations depend on the morphology of said. “So modeling can basically help to fill the gap in these the particles (Fiedler and Violi, 2010). Because the proper regimes that we’re interested in.” functioning of the lipid membrane depends on lipid diffu- sion, this model suggests at least one mechanism by which these particles could cause toxicity. Interactions with Biology Violi and her team have since used this model to test The AMPI calculations generate a list of possible chemi- whether the decision by an international consortium of cal structures that would be present in a carbonaceous regulatory agencies, including EPA, to use C60 fullerenes as material in the environment, but the question then becomes, the only standard for toxicological testing protocols of nano- how do these chemicals and particles interact with biologi- particles in the range of 0.5-1.5 nanometers is scientifically cal systems? The answer, explained Violi, is the province of sound. The team ran the model using the C60 nanoparticle to nanotoxicology at the level of the individual cell, the smallest see if the results reproduced all of the characteristics seen in unit in a living organism, and the point of interaction between model runs that used carbonaceous material from combus- a carbonaceous nanoparticle and a cell is the cell membrane. tion. The answer was no; the reason appears to be that an The cell membrane is a lipid bilayer composed of important parameter is surface area, and the surface area of lipids, cholesterol, and proteins surrounded by water. It is C60 is small compared to that of many other carbonaceous a fluid system, one in which the lipids are always moving nanoparticles.

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49 MODELING AND SIMULATION OF SMALL PARTICLES Violi’s team also modeled the interaction between carbo- naceous particles and lung surfactant, a lipid-based material. They demonstrated that the particles eventually become wrapped in surfactant lipids. “The point is, even if you start with a carbonaceous material, by the time it translocates into the body it’s a totally different animal,” said Violi. Discussion In response to a question from Patricia Thiel of Iowa State University about the existence of experimental data to test the results of these modeling activities, Violi said that her team has used a differential mobility analyzer, which provides information of particle size to sample particles in actual flames. The data from those experiments validate the model in terms of particle size distribution. Currently, they do not have data on the chemical makeup of those particles. Regarding the C60 modeling results, her team is in the process of creating synthetic lipid bilayers and will generate diffu- sion data using commercially available samples of C60 to test their model results. FIGURE 5-2 A “slab” model of aqueous aerosol surfaces. SOURCE: Tobias, 2010. SCALING SIMULATIONS TO R02144 MODEL ENVIRONMENTAL IMPACTS include acid-base chemistry and oxidation of halides at the Figure 5-2 Douglas Tobias and his colleagues at the University of air-water interface and in bulk aqueous solutions. Modeling larger systems,rasterwith less detail, is pos- uneditable albeit bitmap California at Irvine are trying to understand how the surface of a particle differs at the atomic level from the bulk of a sible using a technique known as coarse-graining, which particle and how the interface between that surface and its involves lumping together certain groups of atoms that are environment affects the chemistry of a particle. His group chemically similar into so-called coarse grain beads. This also is starting to explore the more coarse-grained interac- method can drastically reduce the number of particles being tions between particles and biological systems, particularly simulated. Tobias explained how this approach was used to the lipid bilayer that makes up the cell membrane. model a membrane lipid by reducing 138 atoms to 15 beads To Tobias, atomistic modeling means putting every atom (Marrink et al., 2007). Coarse graining, which involves defin- of the system into the model and using molecular dynamics ing different types of interactions, such as polar, mildly polar, to solve the F = ma equation for every particle in the system and charged, can handle mesoscopic systems over microsec- using a ball-and-spring model to represent atoms and bonds. ond timescales with good molecular detail. The calculations continually update the positions and veloci- ties of each atom and generate their trajectories. Understanding Sea Salt Aerosols The aerosol particles Tobias is interested in are typically on the order of 100 nm in size and contains too many atoms to Using these modeling approaches, Tobias’s group has been simulate in its entirety. Because his interest lies primarily in studying the chemistry of sea salt aerosols. Sea salt aerosol the interface between a particle and its environment, Tobias’ is produced when bursting bubbles shoot 100-nanometer to approach is to carve out a little chunk of the particle to create 100-micron droplets of sea water into the atmosphere. The what he calls slab models (Figure 5-2). These slabs can be droplets are primarily concentrated salt solutions consisting decorated with organics and include a variety of molecules mostly of sodium chloride with small amounts of bromide. at the interfaces. The latter is important because bromide is more reactive than Another type of model, used if more detail is required, chloride. Various field and laboratory measurements have replaces the ball-and-spring representation of the atoms and established that these halides in sea salt can be oxidized to bonds with nuclei and electrons, and solves the electronic produce very reactive molecular halogen species (Figure 5-3). structure problem, producing a wave function that generates “Because of the importance of molecular halogens in the the force needed to perform ordinary molecular dynamics atmosphere, this chemistry is important to understand in calculations. This type of model shows that interactions at terms of mechanisms and kinetics in order to find out if an interface are very dynamic and occur on a timescale of a these compounds are going to be atmospherically relevant,” few picoseconds. Current applications for this type of model he explained.

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50 CHALLENGES IN CHARACTERIZING SMALL PARTICLES Tobias became involved in this research because existing important concepts for understanding the behavior of ions kinetic models failed to reproduce the actual production of near interfaces.” And, in fact, this basic picture of increas- molecular chlorine from sea salt that had been measured ing anion adsorption with the halide mass has recently been both in the laboratory and field studies. Missing from these confirmed by x-ray photoelectron spectroscopy (Ghosal et models, Tobias said, was surface chemistry that would make al., 2005). the process heterogeneous rather than homogenous. The next step in Tobias’s modeling effort was to insert Using a molecular dynamic simulation of a concentrated hydroxyl radical. The model shows that hydroxyl radicals sodium chloride solution, Tobias’s modeling studies surpris- also accumulate at the air-water interface and frequently ingly revealed that chloride anions rose to the surface of the encounter chloride ions. Quantum chemical electronic struc- salt solution while sodium tended to stay beneath the surface. ture calculations and molecular dynamics simulations sug- Following the extent of surface exposure of the chloride gest that a mechanism based on the formation of a hydroxyl anions in time showed that 12 percent of the droplet surface radical-chloride complex is plausible. When this mechanism was covered by chloride anions, a finding that contradicted is then used to refine the original model, it accurately repro - more than a century’s worth of conventional wisdom about duced the observed production of chlorine from sea salt the behavior of halide ions at an air-water interface; that (Knipping et al., 2000). is, the ions should stay inside the solution. What appears These models are not just of theoretical use, noted Tobias. to happen, however, is that sodium and fluoride ions are When the sea salt reaction is included in airshed models of repelled from the interface while chloride ions adsorb to the South Coast Air Basin of California, which are used to the interface. Bromide and iodine ions, meanwhile, also calculate regional ozone levels in the Los Angeles Basin, the concentrate at the surface and act as surfactants (Jungwirth adjusted models predict that ozone levels will increase over and Tobias, 2001). most of the basin, and that some regions will experience quite “What we’ve seen is that anion adsorption increases with significant increases at certain times of the day (Knipping ion size and polarizability,” said Tobias. “These are actually and Dabdub, 2003). FIGURE 5-3 Sea salt particles are primarily concentrated sodium chloride, but also contain reactive species such as molecular chlorine. SOURCE: Tobias, 2010. R02144 Figure 5-3

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51 MODELING AND SIMULATION OF SMALL PARTICLES Small Molecule Interactions with Biological Structures are capable of entering the pore of a potassium channel and becoming lodged there, blocking the channel and shutting Recently, Tobias has become interested in modeling how off potassium ion flow (Kraszewski et al., 2010). particles traverse membranes as an approach to understand- ing how particles may cross the blood-brain barrier via a Discussion passive transport process. Preliminary work using coarse- grained molecular dynamics modeling showed that a spheri- In response to a comment by Steve Schwartz about the cal, nonpolar nanoparticle can easily pass through the lipid presence of organic material on the surface and the fact that bilayer of a larger vesicle. In this simple model, the highly this material can form a concentrated film on the surface of curved surface of the vesicle likely plays an important role in sea salt particles, Tobias said that his group has modeled facilitating the easy passage of the inert nanoparticle through particles that include a surfactant layer (Figure 5-4). The the membrane. calculations show that gases can get stuck in the surfactant His group is now working on more systematic studies to layer and therefore undergo additional collisions with the determine which particle properties actually determine its reactive species in solution. In that sense, the surfactant layer ability to cross membranes. This effort has so far shown that can act as a barrier to exclude gases from the initial sea water particle polarity is one feature that exerts a strong influence droplet, but it can also enhance reactivity by trapping those on a particle’s ability to enter and cross membranes. Tobias gas molecules that do enter the droplet. Molecular dynamic plans to explore how variations in size, shape, and surface simulations suggest that these two competing processes actu- chemistry of a particle impact membrane permeability. He ally balance each other out, with the collision rate between also plans to examine the effect on passive transport that reactive trace gases and ions in solution being very similar results from changing membrane composition and adding with and without the surfactant layer. In response to a sec- lipid-embedded proteins to the lipid bilayer. As a closing ond question from Schwartz, Tobias stated that the dynamic comment, he briefly described atomistic modeling work simulations include evaporation. performed by another group that showed that C60 fullerenes FIGURE 5-4 Sea salt particles coated with organic material in smog can lead to an increase in ozone levels. SOURCE: Tobias, 2010. R02144 Figure 5-4 uneditable raster bitmap

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52 CHALLENGES IN CHARACTERIZING SMALL PARTICLES OPEN DISCUSSION clouds given the importance of ice crystals to climate. Violi agreed with Schwartz’s subsequent comment that it could In response to a question from Barbara Finlayson-Pitts prove fruitful to examine the kinetics of ice crystal growth about whether the soot models account for the complex under varying conditions, and Tobias noted that the atomistic organic functionality found on the surface of soot particles, simulation community has undertaken a large effort to model Violi said that the modeling code she described tracks all of ice crystal formation. Stroud added that NASA Ames has a the surface chemistry and all of the functional groups and transmission electron microscope specifically designed to reactive sites on a particle’s surface. The models also repro- take in situ measurements of ice that may provide the kind duce the finding that radical species exist on the surfaces of of data needed to inform and validate modeling efforts. soot particles. Schwartz reiterated his earlier comment about the impor- Mort Lippmann commented that he was encouraged that tance of validating model results with experimental data, modeling efforts are being directed at aqueous droplets such particularly those on the biological impacts of nanomaterials. as hygroscopic sea salt because liquid microdroplets are very Violi remarked that her team always tries to conduct its important from a health perspective. He added, however, modeling work in collaboration with experimentalists. The that he would like to see more work on droplets as well as work on lipid bilayer modeling, however, is a relatively new on particles other than carbon because metal-containing endeavor, and efforts are under way to develop experimental nanoparticles are probably a bigger issue for human health. benchmarks for these models. Tobias agreed with both sets Rhonda Stroud remarked that looking at liquid particles is of comments and suggested some experiments that could a challenge because many of the tools available today are prove useful. For example, x-ray diffraction studies on geared toward studying solid materials. However, efforts stacks of lipid bilayers could look for changes in the density are under way to design microfluidic cells for electron distributions with and without particles. If the particles were microscopy instruments that may be useful for studying soft deuterium labeled, then it would be possible to use neutron materials such as droplets. diffraction to determine the exact location of the particles Steve Schwartz suggested that the modeling community and how they are distributed in the bilayer. might want to pursue knowledge of the ice crystal habitat in