Faculty Bibliography

A health hazard to welders is development of lung cancer. It is believed that this is likely due, in part, to the presence in welding fumes of several hexavalent chromium (Cr[VI]) species, whose solubility depends primarily on which process (i.e., manual metal arc verus metal-inert gas) is used. However, inhalation of Cr alone is uncommon in this setting. Thus, an examination of potential contributions from other coinhalants in creating or enhancing conditions whereby inhaled fume-associated Cr (primarily the insoluble forms) may initiate cancer is critical to increasing our understanding and preventing this particular occupational disease. One major chemical species formed and released during welding is ozone (O3). Though implications of adverse pulmonary effects from individual exposure to Cr or O3 have been investigated, those from simultaneous exposure are unclear. To begin to address whether the carcinogenic potential of insoluble Cr[VI] agents might be enhanced in hosts inhaling mixtures of Cr and O3 versus Cr alone, analyses of total lung Cr burden, Cr retention in lung epithelium and interstitium, and potential shifts in lung cell distribution of Cr from the cytoplasm to nuclei were undertaken in F-344 rats exposed nose-only (5 h/d, 5 d/wk for up to 48 wk) to an extrapolated occupationally relevant level of Cr (360 micrograms Cr/m3 as calcium chromate) alone and in combination with 0.3 ppm O3. Overall, there was only a nominal effect from O3 on Cr retention or on distribution of Cr particles among extracellular sites and within lung cells. However, there were O3-related effects upon mechanisms for clearing the Cr from the deep lung, specifically at the levels of particle uptake and postphagocytic/endocytic processing by macrophages. This O3 exposure-related shift in normal pulmonary clearance might potentially increase the health risk in workers exposed to other insoluble or poorly soluble carcinogenic Cr compounds

This report is part of an extensive study to verify the validity, specificity, and sensitivity of biomarkers of benzene at low exposures and assess their relationships with personal exposure and genetic damage. The study population was selected from benzene-exposed workers in Tianjin, China, based on historical exposure data. The recruitment of 130 exposed workers from glue-making or shoe-making plants and 51 unexposed subjects from nearby food factories was based on personal exposure measurements conducted for 3-4 weeks prior to collection of biological samples. In this report we investigated correlation of urinary benzene metabolites, S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) with personal exposure levels on the day of urine collection and studied the effect of dose on the biotransformation of benzene to these key metabolites. Urinary S-PMA and t,t-MA were determined simultaneously by liquid chromatography-tandem mass spectrometry analyses. Both S-PMA and t,t-MA, but specifically the former, correlated well with personal benzene exposure over a broad range of exposure (0.06-122 ppm). There was good correlation in the subgroup that had been exposed to <1 ppm benzene with both metabolites (P-trend <0.0001 for S-PMA and 0.006 for t,t-MA). Furthermore, the levels of S-PMA were significantly higher in the subgroup exposed to <0.25 ppm than that in unexposed subjects (n=17; P=0.001). There is inter-individual variation in the rate of conversion of benzene into urinary metabolites. The percentage of biotransformation of benzene to urinary S-PMA ranged from 0.005 to 0.3% and that to urinary t,t-MA ranged from 0.6 to approximately 20%. The percentage of benzene biotransformed into S-PMA and t,t-MA decreased with increasing concentration of benzene, especially conversion of benzene into t,t-MA. It appears that women excreted more metabolites than men for the same levels of benzene exposures. Our data suggest that S-PMA is superior to t,t-MA as a biomarker for low levels of benzene exposure

Environmental pollutants, including ambient particulate matter (PM), increase respiratory morbidity. Studies of model PM particles, including residual oil fly ash and freshly generated diesel exhaust particles, have demonstrated that PM affects inflammatory airway responses. Neither of these particles completely represents ambient PM, and therefore questions remain about ambient particulates. We hypothesized that ambient PM of different size fractions collected from an urban environment (New York City air), would activate primary culture human bronchial epithelial cells (HBECs). Because of the importance of granulocyte-macrophage colony-stimulating factor (GM-CSF) on inflammatory and immunomodulatory processes, we focused our studies on this cytokine. We demonstrated that the smallest size fraction (ultrafine/fine; < 0.18 micro m) of ambient PM (11 micro g/cm(2)), upregulated GM-CSF production (2-fold increase). The absence of effect of carbon particles of similar size, and the day-to-day variation in response, suggested that the chemical composition, but not the particle itself, was necessary for GM-CSF induction. Activation of the extracellular signal-regulated kinase and the p38 mitogen-activated protein kinase was associated with, and necessary for, GM-CSF release. These studies serve to corroborate and extend those on model particles. Moreover, they emphasize the role of the smallest size ambient particles in airway epithelial cell responses

BACKGROUND: Depression of peripheral blood cells is a well-known indicator of benzene hematotoxicity. Previous studies of its effects on specific types of blood cells have yielded inconsistent results. We examine hematological findings and their possible relations with exposure markers validated in a recent biomarker project conducted in Tianjin, China. METHODS: Personal benzene exposures were sampled with 3-M organic vapor monitors, and analyzed by gas chromatography. The peripheral blood cells were counted by a cell counter. The WBC differential was manually counted on a total of 900 cells by a US commercial laboratory. RESULTS: A total of 130 exposed workers and 51 age- and gender-matched unexposed subjects were recruited in this study. Benzene exposure levels monitored on the day of biological sample collection for exposed workers ranged from 0.06 to 122 ppm. Their 4-week average and cumulative benzene exposure levels were 0.08-54.5 ppm and 6.1-623.2 ppm-years, respectively. Significant decreases of red blood cells (RBC), white blood cells (WBC), and neutrophils were observed and correlated with both personal benzene exposures and levels of urinary metabolites (S-phenylmercapuric acid and t,t-muconic acid) and albumin adducts of benzene oxide and 1,4-benzeoquinone. CONCLUSIONS: The depressions in RBC, WBC, and neutrophils observed in this study are not only exposure dependent, but also significantly different in the lowest exposed group (at or below 0.25 ppm) compared with unexposed subjects. The results of the present study appear to suggest that lymphocytes may not be more sensitive to chronic benzene exposure than neutrophils

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

A major health hazard to coal miners is development of emphysema following long-term exposure to coal dust. One mechanism underlying development of emphysema is the oxidation of critical methionine (Met) residues in antiproteolytic factor, alpha1-antitrypsin (A1AT) resulting in a protease-antiprotease imbalance in the lung. Several studies have documented an association between the incidence and severity of emphysema among miners and their exposure to crystalline silica (i.e., SiO(2)). However, what remains unclear is the role of other co-inhaled nonemphysematogenic nonoxidant inorganic constituent in disease pathogenesis. We hypothesize that in miners, inhaled trivalent chromium (Cr(3+), the only form of Cr in coal) may potentially affect lung A1AT activity in situ via Cr complexing with Met residues, and thereby exacerbate any SiO(2)-induced imbalance. To ascertain if Cr(3+) could, in fact, affect A1AT activity, in vitro studies were done to assess elastase inhibitory activity following A1AT incubation with soluble Cr(3+). In addition, to determine if Cr(3+) found in the lungs as detoxification products of inhaled hexavalent Cr (Cr(6+)) could affect A1AT in situ, lavages from the lungs of chromate-exposed rats were also analyzed for elastase inhibitory activity The in vitro results indicate that Cr(3+) ions clearly inhibited A1AT function, with an IC50 of 1.1 mM being estimated under the experimental conditions used. The in vivo results indicate that long-term inhalation (12 wk or longer) of chromate-bearing atmospheres also gave rise to significant (i.e., 50-70%) inhibition of the antielastase activity of A1AT. Together, these results clearly suggest that the Cr(3+) present in coal dusts could potentially act to inhibit A1AT activity in the lungs of miners and thereby promote the emphysematogenicity of SiO(2) or of other emphysematogens present as coconstituents in these dusts