Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice

RESEARCH REPORT Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice Günter Oberdörster, Jacob N Finkelstein, Carl Johnston, Number 96 Robert Gelein, Christopher Cox, Raymond Baggs, August 2000 and Alison C P Elder Final Version Includes a Commentary by the Institute’s Health Review Committee HEALTH The Health Effects Institute, established EFFECTS in 1980, is an independent and unbiased INSTITUTE source of information on the health effects of motor vehicle emissions. HEI supports research on all major pollutants, including regulated pollutants (such as carbon monoxide, ozone, nitrogen dioxide, and particulate matter) and unregulated pollutants (such as diesel engine exhaust, methanol, and aldehydes). To date, HEI has supported more than 200 projects at institutions in North America and Europe and has published over 100 research reports. 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STATEMENT Synopsis of Research Report 96 Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice INTRODUCTION shown to induce a potent inflammatory response Many epidemiologic studies, carried out in diverse leading to severe physiologic effects in rats. They 3 locations with varying levels and composition of exposed animals to 100 µg/m carbon and platinum 3 ambient particulate matter and other air pollutants, particles for 6 hours and to 40 µg/m Teflon particles have reported associations between small increases in for 15 minutes. These concentrations are much higher the level of particulate matter and increases in daily than those of ultrafine particles in ambient air. The morbidity and mortality. The strongest associations investigators also evaluated the effects of intratracheal appear to be in the elderly and in individuals with instillation of ultrafine titanium dioxide particles and, cardiopulmonary conditions such as chronic obstruc- in separate experiments, the effects of coexposure to tive pulmonary disease (COPD). However, a biological ultrafine carbon particles and ozone, a gaseous envi- mechanism linking low-level particle exposure and ronmental pollutant that can induce inflammation. pathophysiologic effects has not been established. The investigators tested small numbers of young and Assessing the effects of inhaled particulate matter in old mice and rats that were healthy or had pulmonary appropriate animal models is critical to learning how conditions. They used mice injected with elastase to such pollutants may exert adverse health effects. model humans with emphysema; old Tsk mice, a strain Ambient particulate matter varies in size and chem- with a genetic defect in lung development, to model ical composition. Some scientists have hypothesized the effects of chronic emphysema and age; and mice that very small particles (less than 100 nm in diameter) and rats pretreated with the bacterial product endo- are particularly toxic. Although they constitute only toxin to model humans who have a bacterial airway about 1% to 8% of the mass of particulate matter in infection. Pulmonary inflammation was evaluated by ambient air, these ultrafine particles are present in very measurement of cellular and biochemical parameters high numbers, have greater total surface area than larger in bronchoalveolar lavage fluid, focusing on increases particles, and may deposit in greater numbers in the in the percentage of neutrophils and production of lungs. The Health Effects Institute funded the animal reactive oxygen species, which appeared to be the most study described in this report to address whether and sensitive indicators of a response. Measurements of how ultrafine particles might exert effects in the air- cytokine and chemokine messenger RNA levels in tis- ways. sue extracts as well as histologic assessments were per- formed. APPROACH RESULTS AND CONCLUSIONS Dr Günter Oberdörster, from the University of Roch- ester School of Medicine and Dentistry, and his col- Inhalation of ultrafine carbon or platinum particles, leagues hypothesized that inhaled ultrafine particles or Teflon particles in the absence of Teflon-generated induce an inflammatory response in the airways of gaseous components, did not induce an inflammatory mice and rats and that animals with preexisting response in either young or old healthy mice and rats. airway inflammatory conditions may be particularly Ultrafine particle exposures had limited effects in vulnerable. The investigators focused on inhaled some of the animal models of pulmonary dysfunction carbon and platinum particles because these elements tested and no effect in others. For example, ultrafine are constituents of particles found in urban atmo- carbon and platinum particles induced small inflam- spheres. They also evaluated the effects of Teflon matory responses in both young and old elastase- fumes containing ultrafine Teflon particles, which are treated mice, but ultrafine carbon particles had no not representative of ambient particles but have been effect in the old Tsk mice used to model chronic This Statement, prepared by the Health Effects Institute, summarizes a research project funded by HEI from 1995 to 1999 and conducted by Dr Günter Oberdörster of the University of Rochester School of Medicine and Dentistry, Rochester NY. The following Research Report contains both the detailed Investigators' Report and a Commentary on the study prepared by the Institute's Health Review Committee. Research Report 96 emphysema, either with or without endotoxin pre- induce inflammatory responses in the airways in some treatment. In rats preexposed to endotoxin, ultrafine circumstances: for example, when high doses are depos- carbon particles induced a small inflammatory re- ited in the lower respiratory tract by intratracheal instil- sponse over background airway inflammation in lation or when the particles are combined with young but not old animals. By contrast, a complex sta- potentially toxic gases. tistical analysis of their results led the investigators to In conclusion, the investigators conducted an inter- conclude that older age and a compromised or sensi- esting study in healthy mice and rats and in mice and tized respiratory tract increased sensitivity to ultrafine rats with preexisting airway conditions to address the particle effects in mice and rats. These conclusions are important issue of whether ultrafine particles induce overstated, however, given that the responses to ultra- an inflammatory response in the airways. The find- fine particles were small and occurred only in some ings provide little evidence that inhaled ultrafine par- animal models and certain end points. ticles cause inflammation, however. This may be due Instilling ultrafine titanium dioxide particles directly to limitations in the study’s design, which include into the trachea of mice, a technique that bypasses the small numbers of animals and experiments, uncer- nasal filtering mechanisms and delivers a much higher tainties about the susceptibility of the animal models concentration to the lungs than inhalation, induced a to the effects of ultrafine particles, and the relative strong inflammatory response. Inhalation of ultrafine toxicity of the study particles compared to particles of Teflon fumes in rats also induced a strong inflammatory different chemical composition. These uncertainties response, but only if the fumes contained both ultrafine make it difficult to extrapolate the results of this study Teflon particles and gaseous components. Coexposure to to possible effects of ultrafine particles on humans. ultrafine carbon particles and ozone induced responses Additional research in humans and in a variety of that appeared to be additive, less than additive, or more animal models evaluating multiple endpoints and than additive compared with responses to the separate particles is required to evaluate further whether components, depending on the model and end point ultrafine particles induce inflammatory or other tested. These results suggest that ultrafine particles may adverse health effects. Copyright © 2000 Health Effects Institute, Cambridge MA. Printed at Flagship Press, North Andover MA. Library of Congress Catalog Number for the HEI Report Series: WA 754 R432. The paper in this publication meets the minimum standard requirements of the ANSI Standard Z39.48-1984 (Permanence of Paper) effec- tive with Report Number 21, December 1988, and with Report Numbers 25, 26, 32, 51, 65 Parts IV, VIII, and IX, and 91 excepted. These excepted Reports are printed on acid-free coated paper. CONTENTS Research Report 96 Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice Günter Oberdörster, Jacob N Finkelstein, Carl Johnston, Robert Gelein, Christopher Cox, Raymond Baggs, and Alison C P Elder Departments

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