Ultrafine Particles as a Potential Environmental Health Hazard

Abstract

An association between increased morbidity and mortality and ambient particulate levels <100 µg/m3 (below the national ambient air quality standard of 150 µg/m3) has been found in epidemiologic studies. We suggest that certain ultrafine particles (diameter <50 nm) are the most likely particles to be associated with the observed acute effects. Ultrafine particles are always present in the urban atmosphere in very high numbers (0.5 to >3×105 particles/cm3) yet very low mass concentrations. They are not very stable but are always freshly-generated (eg, combustion processes, tailpipe emissions, gas to particle conversions) and can be highly reactive. We generated model ultrafine particles by heating polytetrafluoroethylene (PTFE, Teflon) to a critical temperature at which high levels of singlet ultrafine particles were produced. Gas phase compounds were at a level known not to cause lung injury. We exposed rats and mice to levels of 1 to 10×105 particles/cm3, equivalent to mass concentrations of about 9 to 90 µg/m3, for up to 30 min. Even the lowest level caused an acute pulmonary inflammatory response while levels of approximately more than 45 µg/m3 caused severe hemorrhagic pulmonary edema with the appearance of large numbers of polymorphonuclear leukocytes (PMNs) in lung lavage samples within 4 h (up to 80% PMN), and mortality occurred. We performed a number of studies to elucidate mechanisms of this dramatic lung injury by determining expression of proinflammatory mediators and antioxidants and evaluating particle disposition (electron energy loss spectroscopy technique) and lung morphology. We found IL-lα, IL-6, TNF-α, inducible nitric oxide synthase, manganese superoxide dismutase, and metallothionein to be upregulated, whereas vascular endothelial growth factor was downregulated in the acute phase of injury. The ultrafine particles translocated rapidly to epithelial, interstitial, and endothelial sites, which showed severe damage including membrane injuries and cell necrosis. Our data are consistent with the following hypothesis: inhaled ultrafine particles depositing in the alveolar region of the lung are not efficiently phagocytized by alveolar macrophages, but rather penetrate into and interact with alveolar epithelial, interstitial, and endothelial cells thereby inducing proinflammatory and anti-inflammatory mediators. Large numbers of activated PM Ns elicited into the lung contribute further to oxidative lung injury. As a result, pulmonary antioxidant proteins are upregulated. We conclude that the ultrafine particle phase of PTFE fume can be highly toxic in the lung and can lead to severe lung injury. It appears to be of importance that these particles are freshly generated and inhaled as singlet particles. We propose that low mass concentrations of ambient ultrafine particles may be causally associated with acute morbidity and mortality observed in epidemiologic studies.