Faculty Bibliography

Epidemiologic studies have shown that exposure to particulate air pollution is associated with short-term increases in cardiovascular morbidity and mortality. These adverse effects of inhaled particulate matter (PM*) may be the indirect result of a PM-induced increase in blood coagulability. This explanation is biologically plausible because prospective studies have shown that increases in blood coagulation parameters are significantly associated with risk of adverse cardiovascular events. We examined the hypothesis that acute exposure to elevated levels of PM causes prothrombotic changes in blood coagulation parameters. Rats with indwelling jugular vein catheters were exposed for 6 hours to filtered air or concentrated ambient PM in New York City air (n = 9 per group per experiment). PM less than 2.5 microm in mass median aerodynamic diameter (PM2.5) was concentrated for animal exposures using a centrifugal concentrator. Blood samples were taken at four time points: before and immediately after exposure and at 12 and 24 hours after the start of exposure. At each time point, six coagulation parameters (platelet count, fibrinogen level, factor VII activity, thrombin-antithrombin complex [TAT] level, tissue plasminogen activator [tPA] activity, and plasminogen activator inhibitor [PAI] activity) were measured as well as all standard blood count parameters. Five concentrated-PM exposure experiments were performed over a period of 8 weeks in the summer of 1999. PM exposure concentrations ranged from 95 to 341 microg/m3. Statistical significance was determined by two-way analysis of variance (ANOVA) on the postexposure data with time and exposure status as main effects. There were no consistent exposure-related effects on any of the end points across the five experiments and no indication of any dose-dependent effects. Most of the statistically significant differences that were observed do not represent adverse effects. Therefore, the results of this study do not indicate that exposure to concentrated ambient PM causes adverse effects on blood coagulation in healthy rats

The predominant exposure route for nickel compounds is by inhalation, and several studies have indicated the correlation between nickel exposure and respiratory cancers. The tumor-promoting effects of nickel compounds are thought to be associated with their transactivation of transcription factors. We have investigated the possible activation of activator protein-1 (AP-1) and nuclear factor KB (NF-kappaB) in mouse C141 epidermal cells and fibroblasts 3T3 and B82, and human bronchoepithelial BEAS-2B cells in response to nickel compound exposure. Our results show that NF-kappaB activity is induced by nickel exposure in 3T3 and BEAS-2B cells. Conversely, similar nickel treatment of these cells did not induce AP-1 activity, suggesting that nickel tumorigenesis occurs through NF-kappaB and not AP-1. We also investigated the role of NF-kappaB in the induction of Cap43 by nickel compounds using dominant negative mutant Ikappabeta kinase b-KM BEAS-2B transfectants

Marked regional differences in prevalence of pneumoconiosis are apparent in the US despite comparable dust exposure. In the present study, we examined the ability of 28 coal samples to release bioavailable iron (BAI) and calcium, as well as other metals such as Cr, Ni, Cu, and Co, from three coal mine regions in Utah (UT), West Virginia (WV), and Pennsylvania (PA), respectively. BAI is defined as iron (both Fe2+ and Fe3+) released by the coals in 10 mM phosphate solution, pH 4.5, which mimics conditions of the phagolysosomes in cells. We found that coals from the UT, WV, and PA regions released average levels of BAI of 9.6, 4658.8, and 12149 parts per million (ppm, w/w), respectively, which correlated well with the prevalence of pneumoconiosis from that region (correlation coefficient r = 0.92). The low levels of BAI in the UT coals were due to the presence of calcite (CaCO3), which was shown to be preferentially acid solubilized before iron compounds. Release of iron by two coal samples from the PA and UT regions was further examined in vitro in human lung epithelial A549 cells. We found that the coal from PA, with a high prevalence of pneumoconiosis, released BAI in a dose-dependent manner, both in tissue culture media and in A549 cells. At 2 microg/cm2, levels of lipid peroxidation induced by the PA coal were increased 112% over control cells at 24 h treatment, and were sustained at this level for 3 days. The coal from UT, with a low prevalence of pneumoconiosis, induced a marginal increase in cellular iron at 5 and 10 microg/cm2 treatments and had no effect on lipid peroxidation. Calcium levels in the cells treated with the PA and UT coals were 8.6 and 11.5 micromoles/10(6) cells, respectively, and were significantly higher than that in the controls (5.3 micromoles/10(6) cells) [corrected]. Our results suggest that the differences in the BAI content in the coals may be responsible for the observed regional differences in the prevalence of pneumoconiosis. Therefore, BAI may be a useful characteristic of coal for predicting coal's toxicity

Few studies have examined the sources of variability in cardiac function measurements in unrestrained animals and the impact of this variability on detection of treatment effects. The heart rate was monitored with implanted ECG transmitters in two groups of male rats, age 7 and 23 mo. Animals were monitored in their cages to determine optimal heart rate sampling frequency and sources of variability in heart rate, including whether there were persistent animal-to-animal differences. Ambient temperature was transiently increased to test whether correction for animal-to-animal differences improved sensitivity for detection of treatment effects. Animal-to-animal differences were statistically significant and accounted for about 18.3% and 11.5% of the total variance for old and young rats, respectively. In both the old and young rats, the heart rate decreased during the heat challenges relative to the control group, but the noncorrected differences were not statistically significant. When pre-exposure baseline values for each rat (average of 72 h prior to the first temperature challenge) were subtracted, the decrease in heart rate was statistically significant during all three challenges for both old and young rats. Subtraction of preexposure heart rate data to correct for baseline differences between animals is important for measuring treatment effects

The explosion and collapse of the World Trade Center (WTC) was a catastrophic event that produced an aerosol plume impacting many workers, residents, and commuters during the first few days after 11 September 2001. Three bulk samples of the total settled dust and smoke were collected at weather-protected locations east of the WTC on 16 and 17 September 2001; these samples are representative of the generated material that settled immediately after the explosion and fire and the concurrent collapse of the two structures. We analyzed each sample, not differentiated by particle size, for inorganic and organic composition. In the inorganic analyses, we identified metals, radionuclides, ionic species, asbestos, and inorganic species. In the organic analyses, we identified polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, pesticides, phthalate esters, brominated diphenyl ethers, and other hydrocarbons. Each sample had a basic pH. Asbestos levels ranged from 0.8% to 3.0% of the mass, the PAHs were > 0.1% of the mass, and lead ranged from 101 to 625 microg/g. The content and distribution of material was indicative of a complex mixture of building debris and combustion products in the resulting plume. These three samples were composed primarily of construction materials, soot, paint (leaded and unleaded), and glass fibers (mineral wool and fiberglass). Levels of hydrocarbons indicated unburned or partially burned jet fuel, plastic, cellulose, and other materials that were ignited by the fire. In morphologic analyses we found that a majority of the mass was fibrous and composed of many types of fibers (e.g., mineral wool, fiberglass, asbestos, wood, paper, and cotton). The particles were separated into size classifications by gravimetric and aerodynamic methods. Material < 2.5 microm in aerodynamic diameter was 0.88-1.98% of the total mass. The largest mass concentrations were > 53 microm in diameter. The results obtained from these samples can be used to understand the contact and types of exposures to this unprecedented complex mixture experienced by the surviving residents, commuters, and rescue workers directly affected by the plume from 11 to 12 September and the evaluations of any acute or long-term health effects from resuspendable dust and smoke to the residents, commuters, and local workers, as well as from the materials released after 11 September until the fires were extinguished. Further, these results support the need to have the interior of residences, buildings, and their respective HVAC systems professionally cleaned to reduce long-term residential risks before rehabitation

Time-series studies have shown that the lag time between elevated particulate air pollution (PM) and increases in cardiovascular-related hospital admissions and death is very short 1 d or less. If PM does cause serious cardiovascular effects shortly after exposure, one would expect to see some physiological change during exposure. In this study, spontaneously hypertensive rats (SHRs) with surgically implanted blood pressure transmitters were exposed to concentrated ambient PM (CAPS) for 4 h to determine whether CAPS inhalation causes immediate effects. The rats were also exposed to sulfuric acid aerosols because acid is one of the components of PM that could potentially activate irritant receptors and cause effects during exposure. Exposure to CAPS caused a striking decrease in respiratory rate that was apparent soon after the start of exposure and stopped when exposure to CAPS ceased. The decrease in respiratory rate was accompanied by a decrease in heart rate. Exposure of the same rats to fine-particle-size sulfuric acid aerosol also caused a significant decrease in respiratory rate similar to the effects of CAPS. Ultrafine acid had the opposite effect on respiratory rate compared to CAPS. Because acids have been shown to evoke sensory irritant responses in rodents, the similarity between the effects of fine acid aerosol and CAPS suggests that CAPS activates airway-irritant receptors during exposure

Recent reports indicate that many of the cytotoxic and health-threatening components of environmental tobacco smoke (ETS) reside in the vapor phase of the smoke. We have reported previously that inhalation of 1,3-butadiene, a prominent vapor phase component of ETS, accelerates arteriosclerotic plaque development in cockerels. In this study we asked whether inhaled acrolein, a reactive aldehyde that is also a prominent vapor-phase component of ETS, damages artery-wall DNA and accelerates plaque development. Cockerels inhaled 0, 1, or 10 ppm acrolein mixed with HEPA-filtered air for 6 hr. Half were killed immediately (day 1 group) for detection of the stable, premutagenic 1,N(2)-propanodeoxyguanosine acrolein adduct (AdG3) in aortic DNA via a (32)P-postlabeling/HPLC method, and half were killed after 10 days (day 10 group) for indirect assessment of adduct repair. In the day 1 group, acrolein-DNA adducts were 5 times higher in the 1 and 10 ppm groups than in HEPA-filtered air controls. However, in the day 10 group, adduct levels in the 1 and 10 ppm acrolein groups were reduced to the control adduct level. For the plaque studies, cockerels inhaled 1 ppm acrolein (6 hr/day, 8 weeks), mixed with the same HEPA-filtered air inhaled by controls. Plaque development was measured blind by computerized morphometry. Unlike butadiene inhalation, acrolein inhalation did not accelerate plaque development. Thus, even though repeated exposure to acrolein alone has no effect on plaque size under the exposure conditions described here, a single, brief inhalation exposure to acrolein elicits repairable DNA damage to the artery wall. These results suggest that frequent exposure to ETS may lead to persistent artery-wall DNA damage and thus provide sites on which other ETS plaque accelerants can act.

As a result of repeated exposures to inhaled toxicants such as zinc oxide (ZnO), numerous individuals acquire tolerance to the exposures and display reduced symptoms. To ascertain whether tolerance is developed in an animal model, NIH-Swiss mice were exposed to 1.0 mg/m(3) ZnO for 1, 3, or 5 days (1X, 3X, or 5X), and polymorphonuclear leukocyte (PMN) and protein levels in bronchoalveolar lavage (BAL) were measured. Mice acquired tolerance to neutrophil infiltration into the lungs, as total PMNs returned near baseline in 5X-exposed animals as compared to that of the 1X exposure group (1X = 2.7 +/- 0.4 x 10(4), 5X = 0.2 +/- 0.1 x 10(4), mean +/- SE, p < 0.05). Development of tolerance to changes in lavageable protein, however, was not observed (1X = 313 +/- 29 microg/ml, 5X = 684 +/- 71 microg/ml, p < 0.05). Tolerance to PMN influx did not persist following re-exposure to ZnO after 5 days of rest. In contrast to ZnO exposure, following single and repeated exposure to aerosolized endotoxin there was development of tolerance to protein in BAL (1X = 174 +/- 71 microg/ml, 5X = 166 +/- 14 microg/ml, p > 0.05), but not to PMN influx (1X = 5.5 +/- 1.7 x 10(4), 13.9 +/- 1.7 x 10(4), p < 0.05). Induction of lung metallothionein (MT) was also observed in mice exposed once or repeatedly exposed to ZnO, suggesting that MT may play a role in its molecular mechanism