2001 Progress Report: The Chemical Toxicology of Particulate MatterEPA Grant Number: R827352C001
Subproject: this is subproject number 001 , 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: The Chemical Toxicology of Particulate Matter
Investigators: Cho, Arthur K. , Froines, John R.
Institution: University of California - Los Angeles
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 2000 through May 31, 2001
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
A central hypothesis of the Southern California Particle Center and Supersite (SCPCS) is that organic constituents associated with particulate matter (PM), including quinones, other organic compounds (polycyclic aromatic hydrocarbons [PAHs], nitro-PAHs, and aldehydes/ketones), and metals, are capable of generating reactive oxygen species (ROS) and acting as electrophilic agents. They have a central role in allergic airway disease including asthma and cardiovascular effects through their ability to generate oxidative stress, inflammation, and immunomodulating effects in the lungs and airways.
The two mechanisms of oxidative stress and electrophilic addition result in impairment and damage to respiratory and cardiac functions. Catalytic action by quinones and related organic compounds and metals represents a key pathway in the toxicity of PM. Quinones produce futile redox cycles as long as reducing equivalents are available, thus enabling continual production of O2-, H2O2, and OH radical. Macrophages and epithelial cells are the principal targets of ROS and the electrophilic agents. We propose that the mechanistic features of the toxicity include activation of NF-kB and AP-1 pathways leading to cytokine and chemokine production and subsequent inflammatory responses, effects on mitochondrial function and apoptosis (see Figure 1). In addition, epidemiologic studies have suggested an association of ambient PM such as PM2.5 with cardiopulmonary diseases and mortality. The 9,10-phenanthroquinone (9,10-PQ) is a potent inhibitor of the neuronal form of nitric oxide synthase (NOS). The 9,10-PQ also inhibits the endothelial form of NOS, which plays a critical role in vascular tone, thereby causing the suppression of nitric oxide (NO)-dependent vasorelaxation of the aorta and a significant increase in blood pressure in rats. Therefore, quinones and other compounds producing ROS (e.g., nitro-PAHs) may contribute to diseases related to vascular dysfunction caused by exposure to urban air particles. In addition to the production of ROS, quinones, PAHs, nitro-PAHs, and related compounds also may undergo electrophilic addition to macromolecules producing complementary toxicity.
Figure 1. Mechanistic Features of Toxicity
Within this mechanistic context we have defined four dosimetric models that represent hypothetical exposure mechanisms to enable quinones, metals, and other organic agents to produce toxicity. These models, outlined in Figure 2, include: (1) the organic compounds and metals that become bioavailable through dissolution and cellular uptake; (2) macrophages and epithelial cells that phagocytize particles and generate ROS and electrophilic chemistry in the intracellular milieu; (3) particles that come in contact with cells followed by dissolution and uptake; and (4) particles that are adsorbed onto cells with subsequent generation of ROS and toxicity. In this latter case, reducing equivalents are required to facilitate the process; elemental carbon may play a role as an electron transfer medium. These hypotheses and mechanistic considerations translate into two related studies:
- Evaluation of the airborne concentrations of different classes of organic compounds, including quinones, nitroaromatics, and carbonyl compounds in ultrafine, fine, and coarse particles collected from diesel engines, freeways, source (source-site with no direct impact from freeways and no demonstrable products of atmospheric chemistry)/receptor (site where products of atmospheric chemistry are important), and Children’s Health Study (CHS) sites in the Los Angeles Basin (LAB) to determine whether the agents are present in measurable concentrations, their distribution as a function of size, their temporal and spatial characteristics, and their relation to toxicity and health effects.
- Development of in vitro chemical assays to assess the reactivity of different PM samples with particular reference to generation of ROS.
Figure 2. Exposure Models
New assay procedures have been developed to expand the ability of the Center to evaluate air pollution samples for compounds of toxicological interest. We have developed a gas chromatography/mass spectrometer (GC/MS) procedure to determine the concentrations of selected quinones in air pollution particles. This procedure has been applied to diesel exhaust particles (DEP) and air pollution samples. We have collected extensive data on quinones and PAHs (see Figures 3a and 3b). There are indications that napthoquinones decline in concentration across the LAB, whereas phenanthroquinones are increased as a result of atmospheric chemistry. These results have toxicological significance when coupled with the results from our in vitro, in vivo, and human epidemiological studies.
Atascadero (source site)
Lompoc (source site)
|SC||University of Southern California (source site)|
|BH||Boyle Heights (source site) – freeway impacted|
|SD||San Dimas (receptor site)|
Upland (receptor site)
Mira Loma (receptor site)
|RV||Riverside (receptor site)|
|Source site – site where little atmospheric chemistry is anticipated|
Receptor site – site on eastern side of Los Angeles Basin where chemistry is expected
We also have been studying the ability of quinones and DEP to catalyze the sulfhydryl mediated reduction of oxygen. This reaction, which generates superoxide, may be useful in predicting the potential toxicity of a sample by its ability to generate free radicals. The reaction will be used to compare small quantities of air pollution samples for their potential toxicity. The limited quantity available of air pollution samples and the need to compare them on a regional basis require a high throughput, highly sensitive procedure. Currently, we are studying yeast as the cellular probe because of its ease of manipulation and its ability to grow in the presence and absence of oxygen. Because the free radical-based toxicity of air pollution is oxygen dependent, this form of toxicity can be evaluated in yeast by determining the oxygen dependent and independent toxicities.
Our research has demonstrated that quinones, DEP, and PM are capable of generating ROS, and we have established quantitative assays to compare toxicity as a function of size, composition, and concentration. We have demonstrated reduction in toxicity when yeast is exposed to quinones, DEP, and PM in the absence of oxygen, suggesting that at least part of the inhibition of growth derives from ROS. Yeast deficient in superoxide dismutase is dramatically impacted by quinones and DEP when the inhibition of growth is evaluated.
Within the next 3 years, the analytical facility will provide comparative analytical data for PAHs, quinones, and other relevant chemical species in air pollution samples from different regions of the LAB. We will provide analytical data on the redox activity of different samples to compare toxicity. Similarly, we will provide toxicological data comparing samples from different regions of the LAB for free radical-based toxicity and for oxygen independent toxicity. We will continue to develop highly sensitive in vitro assays to test relevant hypotheses and make use of genetically altered biological preparations to assess specific mechanistic features.
Journal Articles:No journal articles submitted with this report: View all 10 publications for this subproject
Supplemental Keywords:airborne particulate matter, aerosol, size distribution, particle concentrator, NRC priorities, mechanism, quinones, allergens, bioaerosols, dosimetry, children’s study, indoor exposure, exposure assessment, ultrafine, fine and coarse particles, regional human exposure model, REHEX, asthma, polycyclic aromatic hydrocarbons, PAH, clinical human exposures, source-receptor, measurement error, study design, susceptible populations, geo-code, toxicology, epidemiology, regional modeling, source/receptor analysis, Southern California, Los Angeles Basin, photochemistry, meteorology, trajectory modeling, peroxides, Southern California Particle Center and Supersite, SCPCS, air, geographic area, scientific discipline, health, RFA, susceptibility/sensitive population/genetic susceptibility, biology, risk assessments, genetic susceptibility, health risk assessment, biochemistry, particulate matter, environmental chemistry, mobile sources, state, aerosols, automotive exhaust, epidemiology, California (CA), environmentally caused disease, engine exhaust, environmental hazard exposures, allergen, indoor air, indoor air quality, allergens, particle concentrator, air quality, diesel exhaust, particulate emissions, toxics, human health effects, particulates, sensitive populations, toxicology, diesel exhaust particles, environmental triggers, air pollution, airway disease, atmospheric chemistry, children, automotive emissions, dosimetry, inhaled particles, motor vehicle emissions, asthma triggers, PM characteristics, ambient aerosol, asthma, human exposure, particle transport,, RFA, Health, Scientific Discipline, Air, HUMAN HEALTH, particulate matter, Environmental Chemistry, Air Pollutants, Risk Assessments, Biochemistry, Health Effects, Biology, ambient aerosol, asthma, particulates, human health effects, toxicology, quinones, airway disease, allergic airway disease, air pollution, PAH, human exposure, toxicity, particulate exposure, allergens, breath samples, aerosols, atmospheric chemistry, dosimetry, human health risk, genetic susceptibility, particle transport, particle concentrator
Progress and Final Reports:Original Abstract
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)