Faculty Bibliography

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.

Clinical tolerance to the acute effects of zinc oxide inhalation develops in workers during periods of repeated exposure. The aims of this study were to determine whether clinical tolerance is accompanied by a reduction in the acute pulmonary inflammatory and cytokine responses to zinc oxide exposure and whether tolerance can be demonstrated in sheet metal workers who chronically inhale low levels of zinc oxide. Naive (never-exposed) subjects inhaled 5 mg/m3 zinc oxide on 1 or 3 days and underwent bronchoalveolar lavage 20 hours after the final exposure. Sheet metal workers inhaled zinc oxide on 1 day and control furnace gas on another day. Among naive subjects in whom tolerance was induced, bronchoalveolar lavage fluid percent neutrophils and interleukin-6 (IL-6) levels were significantly decreased compared with subjects who underwent only a single exposure. Sheet metal workers were much less symptomatic, but they still experienced a significant increase in plasma IL-6. The results indicate that clinical tolerance to zinc oxide is accompanied by reduced pulmonary inflammation and that chronically exposed sheet metal workers are not clinically affected by exposure to zinc oxide fume at the Occupational Safety and Health Administration Permissible Exposure Limit. The increase in IL-6 levels observed in the clinically responsive, and to a lesser extent, tolerant, states following zinc oxide inhalation is consistent with the dual role of IL-6 as a pyrogen and anti-inflammatory agent

Significant respiratory-tract exposure to insoluble aluminum compounds, such as alumina (aluminum oxide, Al(2)O(3)), can occur in occupational settings, yet little is known about the temporal pattern of pulmonary clearance of these materials from the lungs with repeated exposures, and potential subsequent translocation to other organs. This study evaluated the clearance pattern of alumina from the lungs of rats, and burdens in selected extrapulmonary organs (brain, bone, liver, spleen, kidney). Rats were instilled with alumina once weekly for 20 wk. Quantification of retention was performed by measuring aluminum burdens in the lungs and extrapulmonary organs during the exposure period, and then weekly for an additional 19 wk after the exposures ended. Lung burdens of aluminum were found to steadily increase during exposure. Clearance of the material following the end of the exposure regime was extremely slow; only approximately 9% of the amount in the lungs following the 20 weekly exposures was cleared by the end of the postexposure period. This study supports the concept of gradual accumulation and long-term retention of aluminum within the respiratory tract of individuals repeatedly exposed to alumina in occupational settings

BACKGROUND: The present study was conducted among Chinese workers employed in glue- and shoe-making factories who had an average daily personal benzene exposure of 31+/-26 ppm (mean+/-SD). The metabolites monitored were S-phenylmercapturic acid (S-PMA), trans, trans-muconic acid (t,t-MA), hydroquinone (HQ), catechol (CAT), 1,2, 4-trihydroxybenzene (benzene triol, BT), and phenol. METHODS: S-PMA, t,t-MA, HQ, CAT, and BT were quantified by HPLC-tandem mass spectrometry. Phenol was measured by GC-MS. RESULTS: Levels of benzene metabolites (except BT) measured in urine samples collected from exposed workers at the end of workshift were significantly higher than those measured in unexposed subjects (P < 0.0001). The large increases in urinary metabolites from before to after work strongly correlated with benzene exposure. Concentrations of these metabolites in urine samples collected from exposed workers before work were also significantly higher than those from unexposed subjects. The half-lives of S-PMA, t,t-MA, HQ, CAT, and phenol were estimated from a time course study to be 12.8, 13.7, 12.7, 15.0, and 16.3 h, respectively. CONCLUSIONS: All metabolites, except BT, are good markers for benzene exposure at the observed levels; however, due to their high background, HQ, CAT, and phenol may not distinguish unexposed subjects from workers exposed to benzene at low ambient levels. S-PMA and t,t-MA are the most sensitive markers for low level benzene exposure.

Epidemiologic studies have provided strong evidence that episodic exposure to ambient particulate matter is associated with increases in morbidity and mortality. These adverse effects have been demonstrated at concentrations far below the National Ambient Air Quality Standard (NAAQS), and thus, the biological plausibility of these effects has been questioned. For the purpose of exposing test animals to relevant and reproducible exposure concentrations of ambient particulate matter (PM), we have developed a simple and inexpensive concentrator system that can concentrate ambient particles 10-fold. A high-volume blower is used to deliver ambient air to the inlet manifold of a centrifugal concentrator and the entrained particles travel along a concentric annulus formed by a stationary solid outer cylinder and a porous inner cylinder rotating at high speed (up to 12,500 rpm). Suction applied at one end of the porous shaft causes the dispersion medium (air) to pass through the porous cylinder and into the shaft. Since the rotational velocity of airborne particles is comparable to that of the rotating cylinder near its surface, the particles move radially outward due to the centrifugal force, in addition to their motion laterally along the cylinder and inward due to the suction of air into the rotating porous cylinder. The particles reach their highest concentration near the outlet manifold, where they enter the exposure chamber under positive pressure (~0.4 cm H2O). Except for coarse particle loss due to impaction and diffusional loss of ultrafine particles in the concentrator, the increase in particle concentration is the ratio of the flow rates for the inlet air and the air delivered to the exposure chamber. We have used the centrifugal concentrator to deliver concentrated ambient urban PM to a nose-only exposure chamber and examined the concentrating effect across ambient particle sizes

Chronic exposure to inhaled cadmium (Cd) has been shown to induce lung tumors in rats (Wistar strain) but not in mice (NMRI strain). The protein metallothionein (MT) plays an important role in Cd detoxification, and it has been suggested that differential inducibility of pulmonary MT may lead to interspecies susceptibility differences to inhaled Cd. Interstrain differences in the pulmonary response of the MT gene to Cd stimuli have not been examined in rats or mice. We compared pulmonary MT expression in Wistar Furth (WF) rats with that in DBA and C57 mice, following a single 3-h exposure to CdO fumes containing 1 mg Cd/m3. Induction of the MT gene was assessed by the levels of MT-I and MT-II transcripts, MT-protein content, and number of MT-labeled alveolar and bronchiolar epithelial cells immediately after Cd exposure and 1, 3, and 5 days later. Control animals were exposed to air/argon furnace gases. We observed differential intra- and interspecies inducibility of the MT gene in the lung following Cd inhalation. DBA mice exhibited greater levels of MT-mRNA, mainly for the MT-I isoform, MT-protein content, and number of MT positive cells relative to C57 mice. WF rats showed lower transcription and translation responses of the MT gene upon Cd stimuli than C57 mice. The present results, in concert with our previous findings of higher lung cell proliferation in Cd-exposed C57 relative to DBA mice, predict greater susceptibility of C57 to the carcinogenic effects of inhaled Cd. Furthermore, the low transcriptional and translation responses of the MT gene to Cd stimuli in WF rats might explain the higher susceptibility of this rat strain to develop malignant lung tumors after chronic exposure to Cd via inhalation. Parallel to our findings in mice, differences in the responsiveness of lung MT gene may exist across rat strains. Thus intraspecies genetic variability in pulmonary MT may influence the susceptibility of rats or mice to lung carcinogenesis induced by inhalation of Cd compounds.

In ambient air, organic chemicals are common constituents of aerosol particles, and many of them are surface-active. If these compounds are present as surface films on aqueous droplets, mass transfer of gaseous molecules into or out of the droplets could be impeded, and the hygroscopic growth of acidic droplets could be reduced. In this work, the effects of organic films on the hygroscopic growth rate of ultrafine H2SO4 aerosols (40-120 nm) were investigated under relative humidity conditions of 20-85% and over time scales of 6 and 10 s. Lauric (C-12 saturated),stearic(C-18,saturated),and oleic acids were chosen as the film coating materials. The experimental results showed that the presence of monolayer films of some fatty acids retards the hygroscopic growth rate of H2SO4 aerosol due to the obstructive effect of the films on the permeation of water vapor. The retardation effects depend on the original film coating thickness. Molecular structure of the film-forming compounds is an important factor for determining the effectiveness of the film. Linear molecules, such as lauric and stearic acids, have stronger effects on mass transport of water vapor than those of nonlinear molecules, such as oleic acid