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2004 Progress Report: Particle Dosimetry

EPA Grant Number: R827352C016
Subproject: this is subproject number 016 , established and managed by the Center Director under grant R827352
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Southern California Particle Center and Supersite
Center Director: Froines, John R.
Title: Particle Dosimetry
Investigators: Phalen, Robert
Current Investigators: Phalen, Robert , Oldham, Michael J.
Institution: University of California - Irvine
EPA Project Officer: Stacey Katz/Gail Robarge,
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 2003 through May 31, 2004
RFA: Airborne Particulate Matter (PM) Centers (1999)
Research Category: Particulate Matter

Description:

Objective:

The Dosimetry Core has two objectives; it is a service core that also performs research. Dosimetry, or the quantification of deposited and/or uncleared particulate mass, is of importance in both the design and interpretation of the Center’s epidemiology and toxicology studies, and for estimating population exposures using air-monitoring data. Two major aspects of dosimetry are : 1) determining the initial amounts of pollutant deposited on specific sites within the respiratory tract, and 2) determining the fates of deposited material with respect to retention, movement and bioavailability. The Dosimetry Core initiates original research to improve relevant dosimetry models and collaborates with other investigators on the grant in order to improve the design, interpretation and impact of their research.

Achieving these goals required maintaining several important assets, including operational computer codes; an appropriate library and literature data base; a qualified computational technician; and hardware for running codes, printing results and preparing publication-quality figures, tables and charts. The Dosimetry Core also initiated a workshop in order to support and guide Center research and to provide coordination with PM-related dosimetry activities outside of the Center.

Progress Summary:

Year 1 Progress Report

The Dosimetry Core was active in several areas including:

  1. Acquiring and installing dosimetry software that is applicable to adults, children and some laboratory animals (rat, mouse and ferret).
  2. Distributing software and software documentation to Center investigators, and providing tutorials on obtaining and using the output.
  3. Helping Center postdoctoral researchers Dr. Jacques and Dr. Yu refine their research on human dose measurements, and bioavailability modeling.
  4. Helping doctoral student Mr. Oldham with his thesis research on validation of Computational Fluid Dynamic (CFD) particle deposition models.
  5. Developing plans for a dosimetry workshop.
  6. Presenting scientific talks on particulate air pollution, including a dosimetry talk at the UCLA Center’s first workshop.

The dosimetry software that is now on hand and functional includes that generated by 1) the National Council on Radiation Protection and Measurements (NCRP), 2) the International Commission on Radiation Protection (ICRP, the software is LUDEP), 3) the Chemical Industry Institute of Toxicology/National Institute of Public Health and the Environment of the Netherlands (CIIT/RIVM, the software is MPPDep), 4) the University of California Irvine (UCI, based on NCRP software), and 5) Fluent Corporation (the CFD software is called FIDAP). Each software package has been tested and is functional. Each package has been found to have unique advantages and limitations. The NCRP model includes adults and children of all ages, provides local deposition doses generation-by-generation, and is the most modifiable (in terms of anatomical data input) for research purposes. The ICRP software includes children and women, and it tracks the transport of inhaled particles leaving the lung, but it does not provide local generation-by-generation doses, and it is not easily manipulated to model individuals. The CIIT/RIVM software, MPPDep (Multiple Path Particle Deposition Model), which became available in July 1999, includes adult males and the laboratory rat. MPPDep calculates particle deposition on both a lobe-by-lobe and generation-by-generation basis, inhalability is an option, ventilation and exposure duration can be specified, and it produces publication-quality graphical output. However, MPPDep is not easy to modify to model individual lung anatomies. We were invited by the writers of MPPDep to suggest improvements, and we have done so. The UCI model is an evolving extension of the original NCRP code. We have expanded the code to include hygroscopic aerosols, tobacco smokes and additional species of laboratory animals (rats, mice and ferrets). This model is our main research tool for improving dosimetry models. The FIDAP software is a very-advanced CFD program that runs on our parallel processor. Specialized training is essential for FIDAP users. This package is capable of solving complex-geometry airflow fields and then tracking individual particles through the geometries. FIDAP has been installed, tested and used to solve flow fields in a 3-generation airway branch that exactly matches physiologically-realistic hollow models in our laboratory. We have performed several particle deposition calculations and compared these predictions with actual particle depositions using monodisperse particles in the hollow laboratory models. Initial results were encouraging in that the computed particle depositions matched the observed patterns, thus holding the promise of eventually providing microdosimetric information at specific sites in the respiratory tract. However, the FIDAP code failed to predict the observed total particle deposition as seen in hollow models.

We acquired 10 copies of MPPDep and 5 copies of the ICRP software and distributed about half of them to Center investigators along with instructions on their use. Thus, Center investigators that were previously not able to easily perform inhaled particle deposition calculations can now do so.

We met several times, both at UCI and at UCLA with Center investigators working on dosimetry-related problems. Dr. Ja ques, who is involved in human clinical exposures, has worked with us to plan measurements of particle deposited dose in individual subjects during exposures to concentrated air pollutant particles. If this can be achieved, the responses of individuals can be correlated with their measured total, and calculated regional particle depositions. This potential sophistication of the human clinical studies is of great interest to us. In addition, Dr. Yu has worked with us to define his research on the bioavailability of organics absorbed in or adsorbed on inhaled fine particles. We helped to define a generic “atmosphere to target tissue” research model that can then be applied to specific cases, such as organic-coated diesel exhaust particles. Such a model is clearly needed.

Our involvement in Mr. Oldham’s doctoral research on CFD modeling has helped him to focus on particles of importance in urban air pollution in the 1 to 10 μm aerodynamic diameter size range. Because CFD models are the only ones capable of computing individual particle deposition locations, as opposed to “smeared” doses, they may be able to explain differences between normal and susceptible subpopulations, if such differences are due to anatomical abnormalities that produce hot spots of particle deposition. Mr. Oldham is also working on converting clinical MRI (Magnetic Resonance Imaging) scans on individuals into forms that can be input into FIDAP for flow solutions and particle deposition calculations. If this effort is successful it will be especially useful for evaluating particle deposition in the upper airways of children and adults with respiratory diseases.

Year 2 Progress Report

Year 2 was not a stellar one for the Dosimetry Core: the projected level of monetary support did not materialize and a planned workshop was preempted. Nevertheless, progress was made and there is considerable interest in planning for the third year of involvement with the SCPCS. The following highlights some Year 2 accomplishments:

  1. Dosimetry Core Staff received the exposure trailer from Dr. Jaques, assured that it was received intact, parked stably, and that the large collection of keys were checked, logged-in, marked and securely stored.
  2. Plans were made with Dr. Kleinman for performing a respiratory-tract morphometric and dosimetric study on the Balb/c freeway-study mice. A preliminary protocol and study design were developed.
  3. All dosimetry software was maintained in a current and functional state. This included renewal of the Computational Fluid Dynamics software and installation of upgrades. Extraction of hourly wind, temperature, dew point and visibility data for 13 weather stations in the L.A. Basin was added as a new capability.
  4. A paper on particle dosimetry in children acknowledging the STAR grant was presented at the Lovelace Respiratory Research Institute Annual Symposium on “Susceptibility Factors in Lung Disease”. An extended abstract was published in the proceedings /program book.
  5. A manuscript acknowledging the STAR grant, “Methods for Modeling Particle Deposition as a Function of Age” was accepted for publication in Respiration Physiology.
  6. A seminar on dosimetry was presented at UCLA.
  7. Plans for an international conference on particulate material were initiated. The American Association for Aerosol Research (AAAR) took the organizational lead, and the U.S. EPA contributed start-up funds. The Dosimetry Core will be centrally involved in directing this important conference, the fourth in a series started in 1994.
  8. Our graduate student, Mr. Oldham completed the experimental portion of his doctoral research on CFD model validation for PM deposition and began writing his thesis. The STAR grant will be acknowledged in journal publications derived from his thesis. It appears that the CFD approach is promising for defining local regions in airways that have high particle depositions. The computed patterns of deposition predicted for 1, 3 and 10 μm aerodynamic diameter particles were consistent with his laboratory experiments. Mr. Oldham shifted his main focus to conducting the rodent exposure “freeway study” with Drs. Kleinman and Sioutas.
  9. At every opportunity, dosimetry discussions occurred between the Dosimetry Core and other SCPCS investigators. Topics included considering body size factors as dose modifiers in the “children’s study”, performing Balb/c lung morphometry, defining the air-to-lung PM transfer coefficient for mice in exposure cages used in the freeway study, and upgrading the wind data during exposures of mice to CAPs.
  10. The Dosimetry Core has been involved in some “outreach” activities. Dr. Phalen served as an outside reviewer for the National Research Council’s third report on PM, and as an external advisory committee site visitor to the University of Rochester PM Center. These activities help to integrate the SCPCS with other research centers.

Year 3 Progress Report

Year 3 was a productive one that focused on the SCPCS theme “Animal and in-vitro studies associated with exposure to PM and co-pollutants.” The following list highlights our accomplishments.

  1. Dosimetry Core staff continued to support work on the mobile exposure unit being readied at UCI. In order to save costs associated with electrical power hookup, a new location adjacent to the Air Pollution lab’s building 238 was selected. The movement of the trailer should accelerate its completion as a mobile exposure laboratory.
  2. The lung morphometry on the Balb/C freeway study mice has been completed. This involved making about 2 dozen in-situ lung casts, selecting 3 casts from ovalbumin sensitized mice and 3 casts from normal mice for detailed morphometric measurements, performing the measurements, and using them to calculate particle deposition efficiencies. In addition, 20 casts were subjected to measurements of a few airways in order to determine the extent to which variations in casting volume influenced the cast airway sizes. The results were interesting. First, the ovalbumin sensitization did not significantly alter airway dimensions. This means that sensitization is not expected to change the deposition of particles in the freeway study, provided that sensitization does not significantly alter breathing patterns during exposure to concentrated air pollutants. Second, variations in casting volume (which are unavoidable due to the tiny cast volumes used in mice) did not significantly change the sizes of airways. Third, the morphometric measurements of the Balb/C mice tracheobronchial trees were significantly different from those obtained by us previously on B6C3F1 mice. This is a novel finding that implies the strain of mouse will significantly influence its deposition dose in an inhalation study. In past dosimetry work, “a mouse was a mouse”, but in the future, the mouse type/strain will also be seen as an important piece of dosimetry information. These findings were significant enough to trigger a paper. The paper, “Dosimetry Implications of Upper Tracheobronchial Airway Anatomy in Two Mouse Strains”, by M.J. Oldham and R.F. Phalen, was submitted to the Anatomical Record in February 2002. The SCPCS EPA Grant was acknowledged as the sponsor.
  3. “Methods for Modeling Particle Deposition as a Function of Age”, by R.F. Phalen and M.J. Oldham, was published in Respiration Physiology 2001;128:119-130. The paper is significant in that it reviews progress and defines needed research required to calculate children’s doses. The paper presents for the first time ten criteria that should be used when comparing and evaluating particle deposition models. The SCPCS EPA Grant was acknowledged.
  4. Our doctoral student, Michael Oldham, completed his program. His research involved validation of a Computational Fluid Dynamic particle deposition model by comparing predictions to bench-top particle depositions in hollow airway models. The thesis, “Comparison of CFD Predictions and Experimental Results for Local Particle Deposition Patterns in Idealized Human Airways”, supports the use of high concentrations of PM in Dr. Nel’s SCPCS research project. The thesis acknowledges the SCPCS Grant. Dr. Oldham began preparing a paper on his research for journal submission.
  5. A dosimetry workshop was held at UCLA on October 26, 2001. The workshop served to bring several SCPCS investigators together to integrate their knowledge on Dosimetric issues related to several of the Center’s themes. Presentations by Drs. Sioutas, Cho, Hinds, Phalen, Yu and Nel were followed by focused discussions. A significant result from the workshop was that the elevated PM concentrations used in Dr. Nel’s in-vitro research could be supported as being realistic representations of local doses in human lung regions during actual exposures in the L.A. Basin as defined by Dr. Hinds’ research. This result is a useful scientific advance, and it also strengthens future publications of Dr. Nel. The workshop also had some implications for the SCPCS epidemiology research in that the importance of understanding “individual” exposures was emphasized. The workshop results were used to contribute to the plans for seeking renewal of the STAR Grant program.
  6. Planning for the international AAAR conference on PM progressed significantly. The health-related portions of the conference are being led by Dr. Phalen with substantial input from EPA’s Dr. John Vandenberg and Dr. Daniel Costa, NYU’s Dr. Morton Lippmann and Dr. Beverly Cohen, and Johns Hopkins’ Dr. Jonathan Samet, among other prominent experts.
  7. A transfer coefficient study was started with nine mice being exposed to 1μm diameter fluorescent tracer particles in the freeway study animal exposure system. The purpose was to quantify deposition in the mice under exposure conditions. Additional tracer particle sizes were planned for Year 4.
  8. At every opportunity, the Dosimetry Core staff engaged SCPCS investigators in dosimetry discussions. The goal was to establish our Center as a leader with respect to PM doses in susceptible populations and compromised animal models.
  9. Substantial difficulty was encountered in preparing research-quality lung casts for the Balb/C mice. The early casts were not curing sufficiently for performing morphometric measurements. After much effort, we discovered that the disposable syringes used to inject silicone rubber casting compound were causing a chemical inhibition of the silicone rubber curing process. To make a long story short, the new “latex free” syringes had a new lubricant that inhibited the curing of silicone rubber. We quickly scoured our department’s syringe supplies and stocked up on a lifetime supply of the old syringes. It is interesting to think about potential interactions of the new “latex-free” syringes with drugs used clinically.

Year 4 Progress Report

Year 4 was a productive one for the Dosimetry Core in its dual role of providing support to the Center and performing research. In the support area, we contributed heavily to the freeway study, including helping with logistics, conducting exposures, performing bioassays, and characterizing the exposure system’s delivery of air pollutants to the mice. Support was provided to Dr. Harkema’s group (from Michigan State University) by helping with lung casting of the Brown Norway rat. We also helped neurotoxicologist, Dr. Campbell of UCI to get neurotoxicity data on mice exposed in the freeway study and prepare an abstract reporting her findings (Campbell, A., Exposure to Particulate Matter in Air Pollution Leads to Inflammatory Responses in Mouse Brain, Abstract, 2003 AAAR PM Meeting). With respect to research, we published a paper describing how mouse variety can significantly affect the deposition of inhaled particles (Oldham, M.J. and Phalen, R.F., Dosimetry Implications of Upper Tracheobronchial Airway Anatomy in Two Mouse Varieties, Anatomical Record, 268:59-65, 2002), and submitted abstracts covering our measurement of the mouse exposures inside custom-designed cages in the freeway study (Oldham, M.J., et al., Performance of a New Mobile Whole Body Mouse Exposure System, Abstract, 2003 AAAR PM Meeting) and the proper doses of particles to use in in-vitro studies that relate to in-vivo exposures (Phalen, R.F. and Oldham, M.J., Selecting Realistic PM Doses for In-vitro Studies, Abstract, 2003 AAAR PM Meeting). Work on a paper with Dr. Andre Nel was begun. This paper will present a clear rationale for the particle doses used in his in-vitro studies. In addition, the core director published a book (Phalen, R.F., “The Particulate Air Pollution Controversy”, Kluwer Academic, 2002), and obtained an NIEHS conference grant for the April-May, 2003 PM conference in Pittsburgh, PA. It was a good year.

Year 5 Progress Report

Year 5 was productive in several ways. The objectives included publication of research results, continuing support of the “freeway study” and preparation and measurement of rodent lung casts in order to produce data on particle doses in toxicology studies. The Dr. Nel paper for which we provided dosimetry-related contributions was published (Li, N, Hao, M., Phalen, R.F., Hinds, W.C. and Nel, A.E., Particulate Air Pollutants and Asthma: A Paradigm for the Role of Oxidative Stress in PM-Induced Adverse Health Effects, Clinical Immunology, 109:250-265, 2003). In support of the Freeway Studies, we submitted two other papers, one describing the performance of the mouse exposure system that is supplied with air pollutants by the particle concentrator, and the other presenting an overview of the knowns and unknowns related to particulate air pollution. Dr. Phalen served as guest editor for two issues of Inhalation Toxicology, Dedicated to the health effects of PM (Vol. 16(6-7) and Vol. 16(Suppl. 1)).

During Year 5 the Dosimetry Core continued to support the freeway studies by assisting during exposures, endpoint acquisition and data analysis.

The preparation and morphometric analysis of lung casts continued throughout the year. Ten rat lungs were cast and stored for measurement, and large-airway morphometry was conducted on casts made in Brown Norway Rats. We concluded that this rat, which is widely used in PM studies, appears to have normal (for rats) large airway structure. Arrangements were discussed with the CIIT Centers for Health Research for incorporating our rodent lung measurements into their widely used dosimetry software MPPD1. The accomplishments were substantial.

Year 6 Progress Report

The final year focused on publications and presentations. Two previously submitted papers were accepted for publication (Oldham, M.J., Phalen, R.F, Robinson, R.J., and Kleinman, M.T., Performance of a Whole Body Mouse Exposure System, Inhalation Toxicology, 16:657-662, 2004; and Phalen, R.F., the Particulate Air Pollution Controversy, Non-Linearity in Biology, Toxicology and Medicine, 2:259-292, 2004). The first paper described doses to mice used in the freeway study and the design of their exposure cages. An interesting feature of the paper was that a Computational Fluid Dynamics model of the cage was successful in simulating field performance. A review paper updating health and atmospheric research on PM was prepared, submitted and accepted for publication (Davidson, C.I., Phalen, R.F., and Solomon, P.A., Airborne Particulate Matter and Human Health: A Review, Aerosol Science and Technology, in press, 2005). This substantial paper covers recent research in the U.S. EPA Particle Centers and other laboratories throughout the world, and identifies key problems and issues that require additional research.

Neurotoxicologist, Dr Campbell’s paper was accepted for publication. Dr. Phalen accepted invitations for two aerosol-dosimetry-related presentations; Particulate Air Pollution: What Should Be Done?, American Occupational Health Conference, May 2005, Washington, D.C.; and Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents: Inhaled Particle Deposition Considerations, National Academy of Sciences, July, 2005, Washington, D.C.). Also, a poster (Phalen, R.F. and Oldham, M.J., Particle Doses for In-Vitro Studies, International Society for Aerosols in Medicine, March, 2005, Perth, Australia) was presented. The poster was an extension of the contributions made by the Dosimetry Core to Dr. Nel’s 2003 paper. A paper for journal publication based on the poster is in preparation.

Conclusions

  1. The aerosol dosimetry software packages (LUDEP and MPPD) in current use that predict inhaled particle deposition efficiencies are both useful for predicting human doses. Although each program gives slightly different values for similar inputs, the differences are within that expected in human populations. Because MPPD1 (latest version) is free (from the CIIT website), user-friendly and includes adults, children and rats, it is recommended for use in the Particle Center. However, LUDEP is also very acceptable.
  2. Computational Fluid Dynamic approaches to solving inhaled article deposition problems have great promise in that individual differences and micro deposition patterns can be addressed. Although such approaches are not adequately validated for us in epidemiology research, they are useful for designing in-vitro particle toxicology studies.
  3. Our morphometry and particle deposition calculations indicate that different mouse strains/varieties can receive different particle doses, even when exposed to the same air pollutant. Thus, dosimetry information in one mouse strain does not necessarily apply to another strain.
  4. Ovalbumin sensitization of Balb/C mice did not significantly change airway dimensions, which simplifies interpretation of particle studies in which sensitized and non-sensitized animals are compared.
  5. Sophisticated dosimetry calculations support the use of relatively large particle doses in in-vitro studies, if particle deposition hot-spots in the lung are believed to relate to effects.
  6. Whole-body aerosol exposures of mice can provide for efficient inhalation of concentrated particulate air pollutants. However, careful design and testing of exposure cages is required.
  7. The current state of modeling inhaled particle deposition in children is strong. Predictions using computer software models are consistent with clinical-setting measurements.
  8. Concentrated airborne particulate matter exposures appear to be capable of increasing inflammatory endpoints in the brains of Balb/C mice (see Campbell, et al., in the list of Publications/Presentations for the Center).

Journal Articles:

No journal articles submitted with this report: View all 6 publications for this subproject


Relevant Websites:

http://www.scpcs.ucla.edu exit EPA

Progress and Final Reports:
2002 Progress Report
2003 Progress Report
Original Abstract
Final Report


Main Center Abstract and Reports:
R827352    Southern California Particle Center and Supersite

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827352C001 The Chemical Toxicology of Particulate Matter
R827352C002 Pro-inflammatory and the Pro-oxidative Effects of Diesel Exhaust Particulate in Vivo and in Vitro
R827352C003 Measurement of the “Effective” Surface Area of Ultrafine and Accumulation Mode PM (Pilot Project)
R827352C004 Effect of Exposure to Freeways with Heavy Diesel Traffic and Gasoline Traffic on Asthma Mouse Model
R827352C005 Effects of Exposure to Fine and Ultrafine Concentrated Ambient Particles near a Heavily Trafficked Freeway in Geriatric Rats (Pilot Project)
R827352C006 Relationship Between Ultrafine Particle Size Distribution and Distance From Highways
R827352C007 Exposure to Vehicular Pollutants and Respiratory Health
R827352C008 Traffic Density and Human Reproductive Health
R827352C009 The Role of Quinones, Aldehydes, Polycyclic Aromatic Hydrocarbons, and other Atmospheric Transformation Products on Chronic Health Effects in Children
R827352C010 Novel Method for Measurement of Acrolein in Aerosols
R827352C011 Off-Line Sampling of Exhaled Nitric Oxide in Respiratory Health Surveys
R827352C012 Controlled Human Exposure Studies with Concentrated PM
R827352C013 Particle Size Distributions of Polycyclic Aromatic Hydrocarbons in the LAB
R827352C014 Physical and Chemical Characteristics of PM in the LAB (Source Receptor Study)
R827352C015 Exposure Assessment and Airshed Modeling Applications in Support of SCPC and CHS Projects
R827352C016 Particle Dosimetry
R827352C017 Conduct Research and Monitoring That Contributes to a Better Understanding of the Measurement, Sources, Size Distribution, Chemical Composition, Physical State, Spatial and Temporal Variability, and Health Effects of Suspended PM in the Los Angeles Basin (LAB)

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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