Faculty Bibliography

The in situ reactions of metal ions/complexes are important in understanding the mechanisms by which environmental and occupational metal particles alter lung immune responses. A better understanding of these reactions in situ will also allow for the improved specificity and controlled toxicity of novel metallocompounds to be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of metals (e.g., chromium, vanadium, nickel) caused altered lung immune cell function and host resistance. The data also suggested that the degree of immunomodulation induced depended not only on the amount of metal deposited, but also the compound used. If specificity governs pulmonary immunomodulatory potential, it follows that physicochemical properties inherent to the metal have a role in the elicited effects. We hypothe-size that major determinants of any metal compound's potential are its redox behavior, valency (generally referred to as oxidation state and considered speciation in chemical literature), and/or solubility. In accord with the extensive work carried out with vanadium (chemical symbol V) compounds showing the importance of form used, differences in potential for a range of V agents (pentavalent [V(V)] insoluble vanadium pentoxide and soluble sodium metavanadate, tetravalent [V(IV)] vanadyl dipicolinate, and trivalent [V(III)] bis(dipicolinato)vanadium) were quantified based on induced changes in local bacterial resistance after host inhalation of each agent at 100 mu g V/m(3) (5 hr/d for 5 d). Differences in effect between V(V) forms indicated that solubility was a critical property in in situ pulmonary immunotoxicity. Among the soluble forms, oxidizing vanadate had the greatest impact on resistance; reducing V(III) altered resistance to a lesser extent. Both the V(IV) and insoluble V(V) had no effect. When data was analyzed in the context of pre-infection lung V burdens, soluble V agents with different oxidation states induced varying responses, supporting the hypothesis that differences in immunomodulatory potential might be attributed to redox behavior or valency. Our findings both provide a basis for understanding why some metals could be a greater health risk than others (when encountered in equal amounts) and will assist in the design of inhalable metallopharmaceuticals by allowing researchers to preempt selection of certain metal ions or complexes for use in such products

Heart rate variability (HRV) is concerned with analysis of the variations in the intervals between heartbeats, known as RR intervals. Commonly used HRV indices may be insensitive in detecting some dynamic changes related to complex autocorrelation functions of the RR intervals. For example, indices SD1 and SD2 of the Poincare plot can be expressed by the variance and first auto-covariance of the signal. The acceleration change index is related to the autocorrelation functions of the series only at the first three lags. We extend the idea of characterizing the sign of differences of a time series to propose a new index called VRL, which is the variance of the run length of the sign of the lagged differentiated time series. The theoretical study shows that VRL is directly related to the autocorrelation functions of the RR series at larger lags. Simulated data are used to validate the theoretical results and assess the power of testing group differences measured with VRL and other HRV indices. The performance of VRL is also evaluated for classifying subjects with normal sinus rhythm and congestive heart failure using the RR intervals taken from the PhysioNet database. We apply the index to RR intervals from an animal study of long-term exposure to particulate matter. The VRL values for the young mice susceptible to atherosclerosis in the control and exposure groups decreased gradually with different slopes after several weeks of exposure. The exposure effect changes in this HRV index estimated by fitting a generalized additive model are significant after 7 weeks of exposure

Particle concentrators are commonly used for controlling exposure levels to ambient ultrafine, fine, and coarse aerosols over a broad range of concentrations. For ultrafine aerosols, these concentrators require water condensation technology to grow and enrich these smaller sized particles (D-a < 100 nm). Because the chemistry of the particles is directly related to their toxicity, any changes induced by ultrafine concentrators on ambient particles need to be better characterized in order to fully understand the results obtained in health exposure studies. Using aerosol time-of-flight mass spectrometry (ATOFMS), the size-resolved chemistry was measured of concentrated ultrafine and accumulation mode (50-300 nm) particles from several particle concentrators with different designs. This is the first report detailing the size-resolved distributions of elemental carbon (EC) and organic carbon (OC) particles sampled from concentrators. Experimental measurements of the single particle mixing state of particles in concentrated versus non-concentrated ambient air show transformations of ultrafine EC particles occur as they become coated with organic carbon (OC) species during the concentration process. Based on relative ion intensities, concentrated ultrafine particles showed a 30% increase in the amount of OC on the EC particles for the same aerodynamic size. An increase in the number fraction of aromatic- and polycyclic aromatic hydrocarbon-containing particles was also observed in both the ultrafine and fine size modes. The most likely explanation for such changes is gas-to-particle partitioning of organic components (e.g., water-soluble organic compounds) from the high volume of air used in the concentrator into aqueous phase ultrafine and fine aqueous particles created during the particle enrichment process

Mainstream cigarette smoke (CS) and wood smoke (WS) were compared in terms of their pulmonary CYP1A1 inducibility. The inducibility was assessed in pulmonary microsomes from rats exposed to freshly generated CS or WS and in rat lung explants treated with extracts of CS or WS total particulate matter (TPM). Mutagenicity in Salmonella typhimurium TA98 and TA100, an effect established for CS and WS in previous studies, was also examined as a test of the biological activity of the smoke samples in the present study. Pulmonary microsomal CYP1A1 activity (as measured by ethoxyresorufin O-deethylase), was induced 4.4-fold and 8.3-fold following exposure of rats to smoke from a single cigarette and three cigarettes, respectively, relative to the activity in control rats. The induction was paralleled by elevated CYP1A1 mRNA level (by northern blot analysis). WS, in contrast to CS, induced neither pulmonary CYP1A1 activity nor mRNA in exposed rats. CYP1A1 protein (by western blot analysis) was induced in cultured rat lung explants by extracts of CS TPM or by a high concentration (496 nM) of benzo[a]pyrene (B[a]P) but not by extracts of WS TPM or a low concentration (0.110 nM) of B[a]P. The induction by high B[a]P concentration was inhibited by extracts of CS or WS TPM, with the inhibition by extracts of WS TPM (75%) being greater than that by extracts of CS TPM (31%). Extracts of CS TPM were as mutagenic as extracts of WS TPM to Salmonella typhimurium TA98 but were more mutagenic than extracts of WS TPM to Salmonella typhimurium TA100. The results show that CS and WS are mutagenic but that WS differs from CS in its inability to induce pulmonary CYP1A1

BACKGROUND: Fine particulate matter (FPM) in ambient air causes premature mortality due to cardiac disease in susceptible populations. OBJECTIVE: Our objective in this study was to determine the most influential FPM components. METHODS: A mouse model of atherosclerosis (ApoE-/-) was exposed to either filtered air or concentrated FPM (CAPs) in Tuxedo, New York (85 microg/m3 average, 6 hr/day, 5 days/week, for 6 months), and the FPM elemental composition was determined for each day. We also examined associations between PM components and mortality for two population studies: National Mortality and Morbidity Air Pollution Study (NMMAPS) and Hong Kong. RESULTS: For the CAPs-exposed mice, the average of nickel was 43 ng/m3, but on 14 days, there were Ni peaks at approximately 175 ng/m3 and unusually low FPM and vanadium. For those days, back-trajectory analyses identified a remote Ni point source. Electrocardiographic measurements on CAPs-exposed and sham-exposed mice showed Ni to be significantly associated with acute changes in heart rate and its variability. In NMMAPS, daily mortality rates in the 60 cities with recent speciation data were significantly associated with average Ni and V, but not with other measured species. Also, the Hong Kong sulfur intervention produced sharp drops in sulfur dioxide, Ni, and V, but not other components, corresponding to the intervention-related reduction in cardiovascular and pulmonary mortality. CONCLUSIONS: Known biological mechanisms cannot account for the significant associations between Ni with the acute cardiac function changes in the mice or with cardiovascular mortality in people at low ambient air concentrations; therefore, further research is needed

ABSTRACT: Particulate air pollution has been associated with respiratory and cardiovascular disease. Evidence for cardiovascular and neurodegenerative effects of ambient particles was reviewed as part of a workshop. The purpose of this critical update is to summarize the evidence presented for the mechanisms involved in the translocation of particles from the lung to other organs and to highlight the potential of particles to cause neurodegenerative effects.Fine and ultrafine particles, after deposition on the surfactant film at the air-liquid interface, are displaced by surface forces exerted on them by surfactant film and may then interact with primary target cells upon this displacement. Ultrafine and fine particles can then penetrate through the different tissue compartments of the lungs and eventually reach the capillaries and circulating cells or constituents, e.g. erythrocytes. These particles are then translocated by the circulation to other organs including the liver, the spleen, the kidneys, the heart and the brain, where they may be deposited. It remains to be shown by which mechanisms ultrafine particles penetrate through pulmonary tissue and enter capillaries. In addition to translocation of ultrafine particles through the tissue, fine and coarse particles may be phagocytized by macrophages and dendritic cells which may carry the particles to lymph nodes in the lung or to those closely associated with the lungs. There is the potential for neurodegenerative consequence of particle entry to the brain. Histological evidence of neurodegeneration has been reported in both canine and human brains exposed to high ambient PM levels, suggesting the potential for neurotoxic consequences of PM-CNS entry. PM mediated damage may be caused by the oxidative stress pathway. Thus, oxidative stress due to nutrition, age, genetics among others may increase the susceptibility for neurodegenerative diseases. The relationship between PM exposure and CNS degeneration can also be detected under controlled experimental conditions. Transgenic mice (Apo E -/-), known to have high base line levels of oxidative stress, were exposed by inhalation to well characterized, concentrated ambient air pollution. Morphometric analysis of the CNS indicated unequivocally that the brain is a critical target for PM exposure and implicated oxidative stress as a predisposing factor that links PM exposure and susceptibility to neurodegeneration.Together, these data present evidence for potential translocation of ambient particles on organs distant from the lung and the neurodegenerative consequences of exposure to air pollutants