title: National Particle Component Toxicity (NPACT) initiative report on cardiovascular effects.
abstract: Epidemiologic and toxicologic studies were carried out in concert to provide complementary insights into the compositional features of ambient particulate matter (PM*) that produce cardiovascular effects. In the epidemiologic studies, we made use of cohort data from two ongoing studies--the Multi-Ethnic Study of Atherosclerosis (MESA) and the Women's Health Initiative--Observational Study (WHI-OS)--to investigate subclinical markers of atherosclerosis and clinical cardiovascular events. In the toxicologic study, we used the apolipoprotein E null (ApoE(-/-)) hypercholesterolemic mouse model to assess cardiovascular effects of inhalation exposure to various atmospheres containing laboratory-generated pollutants. In the epidemiologic studies, individual-level residential concentrations of fine PM, that is, PM with an aerodynamic diameter of 2.5 microm or smaller (PM2.5), PM2.5 components (primarily elemental carbon [EC] and organic carbon [OC], silicon, and sulfur but also sulfate, nitrate, nickel, vanadium, and copper), and the gaseous pollutants sulfur dioxide and nitrogen dioxide were estimated using spatiotemporal modeling and other exposure estimation approaches. In the MESA cohort data, evidence for associations with increased carotid intima-media thickness (CIMT) was found to be strongest for PM2.5, OC, and sulfur, as well as for copper in more limited analyses; the evidence for this was found to be weaker for silicon, EC, and the other components and gases. Similarly, in the WHI-OS cohort data, evidence for associations with incidence of cardiovascular mortality and cardiovascular events was found to be good for OC and sulfur, respectively, and for PM2.5; the evidence for this was found to be weaker for EC and silicon. Source apportionment based on extensive monitoring data in the six cities in the MESA analyses indicated that OC represented secondary formation processes as well as primary gasoline and biomass emissions, that sulfur represented largely secondary inorganic aerosols, and that copper represented brake dust and diesel emissions. In the toxicologic study, hypercholesterolemic mice were exposed for 50 days to atmospheres containing mixed vehicular engine emissions (MVE) consisting of mixed gasoline and diesel engine exhaust or to MVE-derived gases only (MVEG). Mice were also exposed to atmospheres containing sulfate, nitrate, or road dust, either alone or mixed with MVE or MVEG. Sulfate alone or in combination with MVE was associated with increased aortic reactivity. All exposures to atmospheres containing MVE (including a combination of MVE with other PM) were associated with increases in plasma and aortic oxidative stress; exposures to atmospheres containing only sulfate or nitrate were not. Exposure to MVE and to MVEG combinations except those containing road dust resulted in increased monocyte/macrophage sequestration in aortic plaque (a measure of plaque inflammation). Exposure to all atmospheres except those containing nitrate was associated with enhanced aortic vasoconstriction. Exposure to the MVEG was an independent driver of lipid peroxidation, matrix metalloproteinase (MMP) activation, and vascular inflammation. The epidemiologic and toxicologic study designs were intended to complement each other. The epidemiologic studies provided evidence in real-world human settings, and the toxicologic study directly assessed the biologic effects of various pollutant mixtures (in a way that is not possible in epidemiologic studies) by examining endpoints that probably underlie the subclinical and clinical cardiovascular endpoints examined in the epidemiologic studies. The epidemiologic studies were not suited to determining whether the observed associations were caused by direct effects of individual pollutants or by the mixtures in which individual pollutants are found. These studies were consistent in finding that OC and sulfate had the strongest evidence for associations with the cardiovascular disease endpoints, with much weaker evidence for EC and silicon. Both OC and sulfate reflected a large secondary aerosol component. Results from the toxicologic study indicated, for the most part, that MVE and mixtures of MVE and MVEG with other PM pollutants were important in producing the toxic cardiovascular effects found in the study. Further work on the effects of pollutant mixtures and secondary aerosols should allow better understanding of the pollution components and sources most responsible for the adverse cardiovascular effects of air pollution exposure.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, USA. svedal@uw.edu
authors.forename: Sverre
authors.initials: S
authors.lastname: Vedal
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
authors.affiliation: Environmental Respiratory Health Program, and Chemistry and Inhalation Exposure Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: McDonald
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, USA.
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Larson
authors.affiliation: Department of Statistics, University of Washington, Seattle, USA. Department of Epidemiology and Medicine, University of Washington, Seattle, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Sampson
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, USA.
authors.forename: Lianne
authors.initials: L
authors.lastname: Sheppard
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Simpson
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Szpiro
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000397:Air Pollution / Q000009:adverse effects*; D000818:Animals; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology*; D015331:Cohort Studies; D004781:Environmental Exposure / Q000706:statistics & numerical data; D004784:Environmental Monitoring / Q000706:statistics & numerical data*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D052638:Particulate Matter / Q000633:toxicity*; D014481:United States / Q000453:epidemiology
chemical_list: D000393:Air Pollutants; D052638:Particulate Matter