2007 Progress Report: Project 1 -- Pulmonary Metabolic Response

EPA Grant Number: R832414C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R832414
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: San Joaquin Valley Aerosol Health Effects Research Center (SAHERC)
Center Director: Wexler, Anthony S.
Title: Project 1 -- Pulmonary Metabolic Response
Investigators: Fanucchi, Michelle V. , Buckpitt, Alan , Plopper, Charles
Current Investigators: Fanucchi, Michelle V. , Buckpitt, Alan , Plopper, Charles , Winkle, Laura Van
Institution: University of California - Davis
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2011)
Project Period Covered by this Report: October 1, 2006 through September 30, 2007
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

To determine whether the increased pulmonary vulnerability to polycyclic aromatic hydrocarbons (PAHs) in neonates is exacerbated when the PAH is adsorbed to particulate matter. By compromising detoxification mechanisms, particles of mixed composition, such as graphitic carbon and a PAH, graphitic carbon and a transition metal, or graphitic carbon with both a transitional metal and a PAH, will result in more injury than particles composed of only one component.

Progress Summary:

1. Strategy for lung-only administration of 1-nitronaphthalene.
1-Nitronaphthalene is a compound that is not very volatile, making it difficult to create a consistent atmosphere for dose-response studies. In addition, 1-nitronapththalene is also water-insoluble, making it difficult to administer it by instillation. During this period of the grant, we focused on finding a suitable carrier in which to instill 1-nitronaphthalene into the lungs of rats. The best fluid that allows for the solubilization of 1-nitronapthalene with the least amount of irritation is Pluronic F-127, a nonionic, surfactant polyol normally used to facilitate the solubilization of water insoluble dyes into physiological media.

Histological evaluation (Figure 1) of carrier control rats of both intraperitoneal (A) and instillation (C) administration are composed of ciliated (cil) and nonciliated (nc) cells. Intraperitoneal administration of 1-nitronaphthalene (B) resulted in vacuolization (vac) and exfoliation of airway epithelial cells. Intratracheal instillation of 1-nitronaphthalene (D) resulted in increased epithelial thickness and an increase in vacuolated cells present.

Figure 1: Histological comparison of proximal airway epithelial injury by intraperitoneal administration (A, B) and tracheal instillation (C, D) of 1-nitronaphthalene.

Figure 1: Histological comparison of proximal airway epithelial injury by intraperitoneal administration (A, B) and tracheal instillation (C, D) of 1-nitronaphthalene.

2. Comparison of airway epithelial cell cytotoxicity from 1-nitronapthalene (Figure 2) adsorbed to carbon black (Fig. 2: A,B,C) (Monarch® 120, Cabot Corporation, Billerica, MA) or flame generated soot Fig 2: (D,E,F).
We evaluated the cytotoxicity and clearance (24-hr post-insufflation) from a single intra-tracheal insufflation of 2.5 mg submicron carbon black or flame generated soot particles (see particle generation core) adsorbed with 0 or 5% 1-nitronaphthalene in adult rats. To maintain the local position of the particles within the airways, the lungs were inflation-fixed with formalin vapor generated by flowing air through an air stone immersed in 37% formaldehyde at low pressure. The lungs were then evaluated by high resolution histopathology in proximal (A, D), midlevel (B, E) and distal (C, F) airways. Carbon black particles not coated with 1-nitronaphthalene did not cause any appreciable cellular injury to airway epithelium at any airway level and the majority of the particles were cleared from the airways at 24 hours. However, particles coated with 1-nitronaphthalene caused focal areas of exfoliation and cellular injuries in all airways evaluated [proximal (A), mid-level (B) and distal (C) airways] and were not completely cleared from the airways. Flame generated soot not coated with 1-nitronaphthalene did cause cytotoxic injury throughout the airways and this cytotoxicity was increased with adsorption of 1-nitronaphthalene in all airways evaluated [proximal (D), mid-level (E) and distal (F) airways].

Figure 2: Histological comparison of proximal airway epithelial cytotoxicity induced by 1-nitronapthalene adsorbed to carbon black (A,B,C) or flame generated soot (D,E,F) in proximal (A,D) midlevel (B,E) and distal (C,F) airways.

Figure 2: Histological comparison of proximal airway epithelial cytotoxicity induced by 1-nitronapthalene adsorbed to carbon black (A,B,C) or flame generated soot (D,E,F) in proximal (A,D) midlevel (B,E) and distal (C,F) airways.

Future Activities:

The current studies used sub-micron flame-generated soot doped with 1-nitronaphthalene provided by Dr. Ian Kennedy of the Particle Generation, Modification and Characterization Core. We have recently learned that the acetylene flame-generated soot may have metallic contaminants from the acetylene manufacture, so we will evaluate the cytotoxicity of ethylene flame generated soot.

In addition, the administration of 1-nitronaphthalene by aerosol/intra-tracheal instillation has been less than optimal for postnatal animals due to their small size and their intolerance of sedation. Future studies will be performed by utilizing whole animal inhalation of laboratory generated particles and use 1-nitronaphthalene to probe the susceptibility of animals exposed to particles. Using this approach will allow us to generate more data in a reasonable amount of time. It will also facilitate the evaluation of multiple particles (soot + PAH, soot + metal, soot + PAH + metal). In addition, it will allow us to evaluate the susceptibility of postnatal animals to particulate matter.


Journal Articles on this Report : 1 Displayed | Download in RIS Format

Other subproject views: All 43 publications 10 publications in selected types All 8 journal articles
Other center views: All 128 publications 71 publications in selected types All 64 journal articles
Type Citation Sub Project Document Sources
Journal Article Day KC, Plopper CG, Fanucchi MV. Age-specific pulmonary cytochrome P-450 3A1 expression in postnatal and adult rats. American Journal of Physiology-Lung Cellular and Molecular Physiology 2006;291(1):L75-L83. R832414 (2009)
R832414C001 (2007)
R832414C001 (2008)
R832414C001 (Final)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, Air, particulate matter, Environmental Chemistry, Health Risk Assessment, Epidemiology, Risk Assessments, ambient aerosol, lung injury, air toxics, toxicology, long term exposure, lung disease, airway disease, airborne particulate matter, particle exposure, endothelial function, pariculate matter, human exposure, ambient particle health effects, ultrafine particulate matter, epidemiological studies, PM, human health risk

    Progress and Final Reports:

    Original Abstract
  • 2006 Progress Report
  • 2008 Progress Report
  • 2009 Progress Report
  • 2010 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R832414    San Joaquin Valley Aerosol Health Effects Research Center (SAHERC)

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832414C001 Project 1 -- Pulmonary Metabolic Response
    R832414C002 Endothelial Cell Responses to PM—In Vitro and In Vivo
    R832414C003 Project 3 -- Inhalation Exposure Assessment of San Joaquin Valley Aerosol
    R832414C004 Project 4 -- Transport and Fate Particles
    R832414C005 Project 5 -- Architecture Development and Particle Deposition