Research Report (Health Effects Institute)[JOURNAL]
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200 papers
Effects of concentrated ambient particles on normal and hypersecretory airways in rats.
Harkema JR, Keeler G, Wagner J … +7 more , Morishita M, Timm E, Hotchkiss J, Marsik F, Dvonch T, Kaminski N, Barr E
Res Rep Health Eff Inst · 2004 Aug · PMID 15543855
Epidemiological studies have reported that elevated levels of particulate air pollution in urban communities are associated with increases in attacks of asthma based on evidence from hospital admissions and emergency dep...
Epidemiological studies have reported that elevated levels of particulate air pollution in urban communities are associated with increases in attacks of asthma based on evidence from hospital admissions and emergency department visits. Principal pathologic features of chronic airway diseases, like asthma, are airway inflammation and mucous hypersecretion with excessive amounts of luminal mucus and increased numbers of mucus-secreting cells in regions of the respiratory tract that normally have few or no mucous cells (ie, mucous cell metaplasia). The overall goal of the present project was to understand the adverse effects of urban air fine particulate matter (PM2.5; < or = 2.5 pm in aerodynamic diameter)* on normal airways and airways compromised with airway inflammation and excess mucus. Our project was specifically designed to (1) examine the chemical and physical characteristics of PM2.5 and other airborne pollutants in the outdoor air of a local Detroit community with a high incidence of childhood asthma; (2) determine the effects of this community-based PM2.5 on the airway epithelium in normal rats and rats compromised with preexisting hypersecretory airway diseases (ie, animal models of human allergic airway disease--asthma and chronic bronchitis); and (3) identify the chemical or physical components of PM2.5 that are responsible for PM2.5 -induced airway inflammation and epithelial alterations in these animal models. Two animal models of airway disease were used to examine the effects of PM2.5 exposure on preexisting hypersecretory airways: neutrophilic airway inflammation induced by endotoxin challenge in F344 rats and eosinophilic airway inflammation induced by ovalbumin (OVA) challenge in BN rats. A mobile air monitoring and exposure laboratory equipped with inhalation exposure chambers for animal toxicology studies, air pollution monitors, and particulate collection devices was used in this investigation. The mobile laboratory was parked in a community in southwestern Detroit during the summer months when particulate air pollution is usually high (July and September 2000). We monitored the outdoor air pollution in this community daily, and exposed normal and compromised rats to concentrated PM2.5 from this local urban atmosphere. Rats in the inhalation studies were exposed for 1 day or for 4 or 5 consecutive days (10 hours/day) to either filtered air (controls) or concentrated ambient particles (CAPs) delivered by a Harvard ambient fine particle concentrator. Rats were killed 24 hours after the end of the exposure. Biochemical, morphometric, and molecular techniques were used to identify airway epithelial and inflammatory responses to CAPs. Lung lobes were also either intratracheally lavaged with saline to determine cellular composition and protein in bronchoalveolar lavage fluid (BALF) or removed for analysis by inductively coupled plasma-mass spectrometry (ICPMS) to detect retention of ambient PM2.5--derived trace elements. The Harvard concentrator effectively concentrated the fine ambient particles from this urban atmosphere (10-30 times) without significantly changing the major physicochemical features of the atmospheric particles. Daily CAPs mass concentrations during the 10-hour exposure period (0800-1800) in July ranged from 16 to 895 microg/m3 and in September ranged from 81 to 755 microg/m3. In general, chemical characteristics of ambient particles were conserved through the concentrator into the exposure chamber. Single or repeated exposures to CAPs did not cause adverse effects in the nasal or pulmonary airways of healthy F344 or BN rats. In addition, CAPs-related toxicity was not observed in F344 rats pretreated with bacterial endotoxin. Variable airway responses to CAPs exposure were observed in BN rats with preexisting allergic airway disease induced by OVA sensitization and challenge. Only OVA-challenged BN rats exposed to CAPs for 5 consecutive days in September 2000 had significant increases in airway mucosubstances and pulmonary inflammation compared to saline-challenged/air-exposed control rats. OVA-challenged BN rats that were repeatedly exposed to CAPs in July 2000 had only minor CAPs-related effects. In only the September 5-day exposure protocol, PM2.5 trace elements of anthropogenic origin (La, V, and S) were recovered from the lung tissues of CAPs-exposed rats. Recovery of these specific trace elements was greatest in rats with OVA-induced allergic airway disease. Additional laboratory experiments using intratracheal instillations of ambient PM2.5 samples were performed to identify bioactive agents in the CAPs to which rats had been exposed in the inhalation exposure component. Because the most pronounced effects of CAPs inhalation were found in BN rats with OVA-induced allergic airways exposed in September, we used ambient PM2.5 samples that were collected on 2 days during the September CAPs inhalation exposures to use for instillation. Ambient PM2.5 samples were collected, fractionated into soluble and insoluble species, and then compared with each other and with total PM2.5 for their effects in healthy BN rats and those with OVA-induced allergic airway disease. Intratracheal instillation of the insoluble fraction of PM2.5 caused mild neutrophilic inflammation in the lungs of healthy rats. However, total PM2.5 or the soluble or insoluble fractions instilled in rats with OVA-induced airway inflammation did not enhance the inflammation or the airway epithelial remodeling that was evident in some of the BN rats exposed to CAPs by inhalation. Therefore, the results from this instillation component did not suggest what fractions of the CAPs may have been responsible for enhancing OVA-induced airway mucosubstances and pulmonary inflammation observed in the inhalation exposure component. In summary, inhaled CAPs-related pulmonary alterations in the affected OVA-challenged rats appeared to be related to the chemical composition, rather than the mass concentration, to which the animals were exposed. Results of the trace element analysis in the lungs of CAPs-exposed BN rats exposed in September suggested that air particles derived from identified local combustion sources were preferentially retained in allergic airways. These results demonstrate that short-term exposures to CAPs from this southwestern Detroit community caused variable responses in laboratory rats and suggest that adverse biological responses to ambient PM2.5 may be associated more closely with local sources of particles and weather patterns than with particle mass.
A case-crossover analysis of fine particulate matter air pollution and out-of-hospital sudden cardiac arrest.
Checkoway H, Levy D, Sheppard L … +3 more , Kaufman J, Koenig J, Siscovick D
Res Rep Health Eff Inst · 2000 Dec · PMID 15478496
Numerous recent epidemiologic studies report increases in the daily incidence of cardiovascular disease mortality and morbidity related to increases in daily levels of fine particulate matter (PM)* air pollution. This st...
Numerous recent epidemiologic studies report increases in the daily incidence of cardiovascular disease mortality and morbidity related to increases in daily levels of fine particulate matter (PM)* air pollution. This study sought to evaluate the possible association between the occurrence of out-of-hospital sudden cardiac arrest (SCA) and daily PM levels in the Seattle metropolitan area. The underlying hypothesis was that PM exposure may act as a cardiovascular trigger for SCA. A case-crossover study was conducted among 362 SCA cases identified by paramedics from October 1988 through June 1994. Cases were King County WA residents who were married, aged 25 to 74 years at the time of their SCA, with no prior history of clinically recognized heart disease or other life-threatening comorbid conditions. Daily averages of regional PM monitoring data for nephelometry measures of PM (reported in units of bsp, referred to as coefficient of light scattering) and PM10 (particulate matter 10 microm or smaller in aerodynamic diameter) from three monitoring sites were used as indicators of exposure. In the case-crossover analysis, PM levels during index times of cases within the five days preceding an SCA were compared with PM levels at referent days, defined as the same days of the week during the month of SCA occurrence. Lag periods for index days of 0 to 5 days were investigated. The estimated relative risk (RR) at a lag of 1 day for an interquartile range (IQR) change in nephelometry (0.51 bsp) was 0.893 (95% confidence interval [CI] 0.779-1.024). Varying the lag period had only minimal change on the observed association. The estimated relative risk at a lag of 1 day for an IQR change of PM10 (19.3 microg/m3) was 0.868 (95% CI 0.744-1.012). There was no evidence of confounding by ambient daily exposures to carbon monoxide or sulfur dioxide. Analysis of effect modification by individual-level variables, including age, cigarette smoke exposure, physical activity, and other risk or protective factors for cardiovascular disease did not reveal any susceptible subgroups. The null results of this study may be due to several factors; these include: the highly selected nature of this SCA case series; the fact that cases were free of prior clinically recognized heart disease or major life-threatening comorbidity; and the possibility that PM exposures at the relatively low levels seen in the Seattle metropolitan area do not trigger cardiovascular toxic mechanisms that culminate in SCA.
The National Morbidity, Mortality, and Air Pollution Study. Part III: PM10 concentration-response curves and thresholds for the 20 largest US cities.
Daniels MJ, Dominici F, Zeger SL … +1 more , Samet JM
Res Rep Health Eff Inst · 2004 May · PMID 15457982
Numerous studies have shown a positive association between daily mortality and particulate air pollution, even at concentrations below regulatory limits. These findings have motivated interest in the shape of the concent...
Numerous studies have shown a positive association between daily mortality and particulate air pollution, even at concentrations below regulatory limits. These findings have motivated interest in the shape of the concentration-response relation. We developed flexible modeling strategies for time-series data that include spline and threshold concentration-response models. We applied these models to daily time-series data for the 20 largest US cities for 1987 through 1994, using concentration of particulate matter less than 10 microm in aerodynamic diameter (PM10*) as the exposure measure. The spline model showed a linear relation without indicating a threshold for the relative risks of death for all causes (total deaths) and for cardiovascular-respiratory causes in relation to PM10 concentration. By contrast, for causes other than cardiovascular-respiratory, the relative risk did not increase until the concentration reached approximately 50 microg/m3 PM10. For total mortality, a linear model without threshold was preferred to the threshold model and to the spline model, using the value of the Akaike information criterion (AIC). The findings were similar for combined cardiovascular and respiratory deaths. These findings indicate that linear models without a threshold are appropriate for assessing the effect of particulate air pollution on daily mortality even at current ambient levels.
Manganese toxicokinetics at the blood-brain barrier.
Yokel RA, Crossgrove JS
Res Rep Health Eff Inst · 2004 Jan · PMID 15043400
Increased manganese (Mn) use in manufacturing and in gasoline has raised concern about Mn-induced parkinsonism. Previous research indicated carrier-mediated brain entry but did not assess brain efflux. Using in situ rat...
Increased manganese (Mn) use in manufacturing and in gasoline has raised concern about Mn-induced parkinsonism. Previous research indicated carrier-mediated brain entry but did not assess brain efflux. Using in situ rat brain perfusion, we studied influx across the blood-brain barrier (BBB*) of three predominant plasma Mn species available to enter the brain: Mn2+, Mn citrate, and Mn transferrin. Our results suggested transporter-mediated uptake of these species. The uptake rate was greatest for Mn citrate. Our results using the brain efflux index method suggested that diffusion mediates distribution from rat brain to blood. To characterize the carriers mediating brain Mn uptake, we used rat erythrocytes, an immortalized murine BBB cell line (b.End5), primary bovine brain endothelial cells (bBMECs), and Sprague Dawley and Belgrade rats. Studies with bBMECs and b.End5 cells suggested concentrative brain Mn2+ and Mn citrate uptake, respectively, consistent with carrier-mediated uptake. Mn2+ uptake positively correlated with pH, suggesting mediation by an electromotive force. Mn2+ uptake was not inhibited by iron or the absence of divalent metal transporter 1 (DMT-1) expression, suggesting an iron-transporter-independent mechanism. Mn2+ uptake inversely correlated with calcium and was affected by calcium channel modulators, suggesting a role for calcium channels. Rat erythrocyte results suggested monocarboxylate transporter 1 (MCT1) and anion exchange transporters do not mediate Mn citrate brain uptake. Considering carrier-mediated brain influx (but not efflux), repeated excessive Mn exposure should produce brain accumulation. Further work is necessary to identify the specific transporter or transporters mediating Mn distribution across the BBB.
Peroxides and macrophages in the toxicity of fine particulate matter in rats.
Laskin DL, Morio L, Hooper K … +3 more , Li TH, Buckley B, Turpin B
Res Rep Health Eff Inst · 2003 Dec · PMID 15035594
Epidemiologists have observed a positive association between human morbidity and mortality and the atmospheric concentrations of fine particulate matter (PM), but the mechanisms underlying the toxic effects of PM have no...
Epidemiologists have observed a positive association between human morbidity and mortality and the atmospheric concentrations of fine particulate matter (PM), but the mechanisms underlying the toxic effects of PM have not been elucidated. Various components of ambient PM have been implicated in toxicity (including ultrafine particles, transition metals, organics and oxidants). Our research focused on hydrogen peroxide (H2O2). We speculated that fine PM transports H2O2 into the lower lung, leading to tissue injury and to accumulation and activation of macrophages in these regions. The macrophages release cytotoxic mediators and proinflammatory cytokines that contribute to the pathogenesis of tissue injury. To test this hypothesis, we conducted studies to determine (1) whether tissue injury induced by aerosols is mediated by cytotoxic H2O2 carried into the lower lung by fine particles and (2) whether exposure of rats to fine PM leads to accumulation of activated macrophages in the lung. For our studies, systems were designed to generate model atmospheric fine PM and atmospheric peroxides consisting of an ammonium sulfate [(NH4)2SO4] aerosol (mass median diameter, 0.46 +/- 0.14 microm) and H2O2. We also constructed a 6-port nose-only exposure chamber. Female Sprague Dawley rats were exposed for 2 hours to aerosols consisting of (NH4)2SO4 (430 microg/m3), (NH4)2SO4 + 10, 20 or 100 ppb H2O2, vapor-phase H2O2 (10, 20 or 100 ppb), or particle-free air. Studies using oxygen-18 (18O)-labeled H2O2 were conducted to validate the transport of H2O2 into the lower lung with (NH4)2SO4. Rats were killed immediately (0 hours) or 24 hours after exposure. Compared with control animals, inhalation of (NH4)2SO4 and H2O2, alone or in combination, had no major effect on cell number or viability, protein content, or lactate dehydrogenase (LDH) levels in bronchoalveolar lavage (BAL) fluid collected either immediately or 24 hours after exposure. However, electron microscopy revealed that a larger number of neutrophils in pulmonary capillaries adhered to the vascular endothelium, especially in lungs of rats exposed to (NH4)2SO4 + H2O2. Inhalation of (NH4)2SO4 + H2O2 was also found to be associated with altered macrophage functional activity. Thus, exposing rats to (NH4)2SO4 + 20 ppb H2O2 or 20 ppb H2O2 alone caused a level of tumor necrosis factor alpha (TNF-alpha) production by lung macrophages that was higher than in controls. This higher level was observed immediately after exposure and persisted for at least 24 hours. Greater TNF-alpha production was also detected 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2. Immediately after rats inhaled (NH4)2SO4 + 10 ppb H2O2 or 20 ppb H2O2 alone, we also observed a transiently higher production of superoxide anion (O2-) by alveolar macrophages. Macrophages isolated 24 hours after exposure to 20 ppb H2O2 also produced larger quantities of superoxide anion. In contrast, immediately after exposure, macrophages from rats exposed to (NH4)2SO4 + 10 ppb H2O2 or to 20 ppb H2O2 alone generated less nitric oxide (NO). Reduced nitric oxide production was also observed 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2 or to 10 or 20 ppb H2O2 alone. Reduced nitric oxide production may have been due to superoxide anion-driven formation of peroxynitrite (ONOO-) anions. In this regard, nitrotyrosine, an in vivo marker of peroxynitrite, was detected in lung tissue immediately after rats were exposed to (NH4)2SO4 + H2O2 or to H2O2 alone (10 or 20 ppb). We also found that alveolar macrophages from rats exposed to (NH4)2SO4 + H2O2 showed a greater expression of the antioxidant enzyme heme oxygenase-1 (HO-1) when stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Similar results were observed after exposure of rats to an organic peroxide aerosol (cumene hydroperoxide). Taken together, the results of our studies demonstrate that biological effects of inhaled H2O2 are augmented by fine PM. Moreover, tissue injury induced by (NH4)2SO4 + H2O2 may be related to altered production of cytotoxic mediators by alveolar macrophages. Determining the relevance of these toxicologic results to human health will be important in future studies for evaluating the risk of exposure.
Controlled exposures of healthy and asthmatic volunteers to concentrated ambient particles in metropolitan Los Angeles.
Gong H, Sioutas C, Linn WS
Res Rep Health Eff Inst · 2003 Dec · PMID 14738210
Epidemiologic studies report health effects associated with exposure to ambient particulate matter (PM), but underlying biologic mechanisms remain unclear. We evaluated pulmonary and systemic effects in twelve healthy hu...
Epidemiologic studies report health effects associated with exposure to ambient particulate matter (PM), but underlying biologic mechanisms remain unclear. We evaluated pulmonary and systemic effects in twelve healthy human adult and twelve asthmatic volunteers exposed once for 2 hours in a whole-body chamber to approximately 200 microg/m3 concentrated ambient particles (CAPs) in the fine (< 2.5 microm) size range and once to filtered air. Neither healthy nor asthmatic subjects showed significant changes in symptoms, spirometry, or routine hematologic measurements attributable to CAPs exposure compared with filtered air. Both groups showed CAPs-related (1) decreases of columnar cells in induced sputum after exposure, (2) increases in certain blood mediators of inflammation (ie, soluble intercellular adhesion molecule 1 [ICAM-1] and interleukin [IL] 6 [marginally significant in asthmatic subjects only]), and (3) parasympathetic stimulation of heart rate variability (HRV). In the asthmatic group, systolic blood pressure modestly increased during filtered air exposure and decreased during CAPs exposure, whereas the pattern was reversed in the healthy group. In summary, this study measured a large number and wide range of biologic endpoints on a relatively small number of healthy and asthmatic volunteers and found few biologic endpoints that responded to CAPs and filtered air exposures with significantly different values. However, observed changes in some mediators of inflammation in blood and changes in HRV were consistent with PM-related effects reported from epidemiologic studies. They suggest that exposure to concentrated PM 2.5 pm or smaller in aerodynamic diameter (PM2.5) tends to elicit more systemic than pulmonary effects. This investigation is one of the first to apply concentrator-exposure technology in a high-risk group (subjects with asthma). Further studies of responses to CAPs that involve other biologic endpoints, other PM size modes, and subjects with other risk factors are needed.
Health effects of acute exposure to air pollution. Part II: Healthy subjects exposed to concentrated ambient particles.
Holgate ST, Devlin RB, Wilson SJ … +1 more , Frew AJ
Res Rep Health Eff Inst · 2003 Dec · PMID 14738209
The purpose of this study was to assess the impact of short-term exposure to concentrated ambient particles (CAPs*) on lung function and on inflammatory parameters in blood and airways of healthy human subjects. Particle...
The purpose of this study was to assess the impact of short-term exposure to concentrated ambient particles (CAPs*) on lung function and on inflammatory parameters in blood and airways of healthy human subjects. Particles were concentrated from the ambient air in Chapel Hill, North Carolina, using a Harvard/EPA (US Environmental Protection Agency) ambient fine particle concentrator (HAPC). Each of 38 subjects was exposed either to filtered air (n = 8) or to CAPs (n = 30) for two hours, during which all subjects intermittently exercised. Blood was obtained immediately before and 18 hours after exposure. Also at 18 hours after exposure, viable bronchial biopsy tissues and lavage samples were obtained from 10 CAPs-exposed and 7 control subjects by fiberoptic bronchoscopy. To balance these two groups, additional biopsy tissues were obtained from 4 control subjects participating in an identical protocol for another study. For the CAPs-exposed group, the concentration of particulate matter measuring 2.5 microm or less in aerodynamic diameter (PM2.5) in the exposure aerosols varied from 23.1 to 311.1 microg/m3; for the filtered air group, mean particle concentration was 2.9 microg/m3. For comparative analyses, the CAPs-exposed subjects were separated into three tertiles on the basis of the final concentration of particles to which they were exposed. Lung function, assessed by spirometry and plethysmography before and immediately after exposure, was unaffected by CAPs. Of the inflammatory parameters studied in blood, subjects exposed to CAPs showed mean increases in fibrinogen of 40 to 48 mg/dL with no obvious differentiation by dose, whereas subjects exposed to filtered air showed no change; red and white blood cell counts were unaffected by CAPs exposure. In bronchoalveolar lavage fluid from CAPs-exposed subjects, neutrophils showed a dose-dependent increase both when analyzed as an absolute cell count and as a percentage of total lavaged cells. Bronchial biopsy tissues from 10 CAPs-exposed subjects and 11 control subjects did not show any consistent effect of CAPs exposure on cell counts or adhesion molecule expression. We conclude that CAPs induced a modest degree of airway inflammation as judged by lavage, but this effect was not reflected in biopsy tissues from proximal airways. This discrepant finding may mean that the inflammatory effect of CAPs occurs in more distal airways or that the health effects of PM are driven by processes other than those investigated in this study.
Health effects of acute exposure to air pollution. Part I: Healthy and asthmatic subjects exposed to diesel exhaust.
Holgate ST, Sandström T, Frew AJ … +6 more , Stenfors N, Nördenhall C, Salvi S, Blomberg A, Helleday R, Söderberg M
Res Rep Health Eff Inst · 2003 Dec · PMID 14738208
The purpose of this study was to assess the impact of short-term exposure to diluted diesel exhaust on inflammatory parameters in human airways. We previously exposed control subjects for 1 hour to a high ambient concent...
The purpose of this study was to assess the impact of short-term exposure to diluted diesel exhaust on inflammatory parameters in human airways. We previously exposed control subjects for 1 hour to a high ambient concentration of diesel exhaust (particle concentration 300 pg/m3--a level comparable with that found in North Sea ferries, highway underpasses, etc). Although these exposures did not have any measurable effect on standard indices of lung function, there was a marked neutrophilic inflammatory response in the airways accompanied by increases in blood neutrophil and platelet counts. Endothelial adhesion molecules were upregulated, and the expression of interleukin 8 messenger RNA (IL-8 mRNA*) was increased in a pattern consistent with neutrophilia. Individuals with asthma have inflamed airways and are clinically more sensitive to air pollutants than are control subjects. The present study was designed to assess whether this clinical sensitivity can be explained by acute neutrophilic inflammation or an increase in allergic airway inflammation resulting from diesel exhaust exposure. For this study, we used a lower concentration of diesel exhaust (100 microg/m3 PM10) for a 2-hour exposure. At this concentration, both the control subjects and those with asthma demonstrated a modest but statistically significant increase in airway resistance following exposure to diesel exhaust. This increase in airway resistance was associated with an increased number of neutrophils in the bronchial wash (BW) fluid obtained from control subjects (median after diesel exhaust 22.0 vs median after air 17.2; P = 0.015), as well as an increase in lymphocytes obtained through bronchoalveolar lavage (BAL) (15.0% after diesel exhaust vs 12.3% after air; P = 0.017). Upregulation of the endothelial adhesion molecule P-selectin was noted in bronchial biopsy tissues from control subjects (65.4% of vessels after diesel exhaust vs 52.5% after air). There was also a significant increase in IL-8 protein concentrations in BAL fluid and IL-8 mRNA gene expression in the bronchial biopsy tissues obtained from control subjects after diesel exhaust exposure (median IL-8 expression 65.7% of adenine phosphoribosyl transferase [APRT] gene expression value after diesel exhaust vs 51.0% after air; P = 0.007). There were no significant changes in total protein, albumin, or other soluble inflammatory markers in the BW or BAL fluids. Red and white blood cell counts in peripheral blood were unaffected by diesel exhaust exposure. Airway mucosal biopsy tissues from subjects with mild asthma (defined as forced expiratory volume in 1 second [FEV1] greater than or equal to 70% of the predicted value) showed eosinophilic airway inflammation after air exposure compared with the airways of the corresponding control subjects. However, among the subjects with mild asthma, diesel exhaust did not induce any significant change in airway neutrophils, eosinophils, or other inflammatory cells; cytokines; or mediators of inflammation. The only clear effect of diesel exhaust on the airways of subjects with asthma was a significant increase in IL-10 staining in the biopsy tissues. This study demonstrated that modest concentrations of diesel exhaust have clear-cut inflammatory effects on the airways of nonasthmatic (or control) subjects. The data suggest a direct effect of diesel exhaust on IL-8 production leading to upregulation of endothelial adhesion molecules and neutrophil recruitment. Despite clinical reports of increased susceptibility of patients with asthma to diesel exhaust and other forms of air pollution, it does not appear that this susceptibility is caused either directly by induction of neutrophilic inflammation or indirectly by worsening of preexisting asthmatic airway inflammation. The increased level of IL-10 after diesel exhaust exposure in airways of subjects with asthma suggests that this pollutant may induce subtle changes in airway immunobiology. This is an important topic for further investigation. Other possible explanations for the apparent lack of response to diesel exhaust among subjects with asthma include (1) the time course of the response to diesel may differ from the response to allergens, which peaks 6 to 8 hours after exposure; (2) a different type of inflammation may occur that was not detectable by the standard methods used in this study; and (3) the increased sensitivity of patients with asthma to particulate air pollution may reflect the underlying bronchial hyperresponsiveness found in asthma rather than any specific increase in inflammatory responses.
Biomarkers in Czech workers exposed to 1,3-butadiene: a transitional epidemiologic study.
Albertini RJ, Srám RJ, Vacek PM … +25 more , Lynch J, Nicklas JA, van Sittert NJ, Boogaard PJ, Henderson RF, Swenberg JA, Tates AD, Ward JB, Wright M, Ammenheuser MM, Binkova B, Blackwell W, de Zwart FA, Krako D, Krone J, Megens H, Musilová P, Rajská G, Ranasinghe A, Rosenblatt JI, Rössner P, Rubes J, Sullivan L, Upton P, Zwinderman AH
Res Rep Health Eff Inst · 2003 Jun · PMID 12931846
A multiinstitutional, transitional epidemiologic study was conducted with a worker population in the Czech Republic to evaluate the utility of a continuum of non-disease biological responses as biomarkers of exposure to...
A multiinstitutional, transitional epidemiologic study was conducted with a worker population in the Czech Republic to evaluate the utility of a continuum of non-disease biological responses as biomarkers of exposure to 1,3-butadiene (BD)* in an industrial setting. The study site included two BD facilities in the Czech Republic. Institutions that collaborated in the study were the University of Vermont (Burlington, Vermont, USA); the Laboratory of Genetic Ecotoxicology (Prague, the Czech Republic); Shell International Chemicals, BV (Amsterdam, The Netherlands); the University of North Carolina at Chapel Hill (Chapel Hill, North Carolina, USA); University of Texas Medical Branch at Galveston (Galveston, Texas, USA); Leiden University (Leiden, The Netherlands); and the Health and Safety Laboratory (Sheffield, United Kingdom). Male volunteer workers (83) participated in the study: 24 were engaged in BD monomer production, 34 in polymerization activities, and 25 plant administrative workers served as unexposed control subjects. The BD concentrations experienced by each exposed worker were measured by personal monitor on approximately ten separate occasions for 8-hour workshifts over a 60-day exposure assessment period before biological samples were collected. Coexposures to styrene, benzene, and toluene were also measured. The administrative control workers were considered to be a homogeneous, unexposed group for whom a series of 28 random BD measurements were taken during the exposure assessment period. Questionnaires were administered in Czech to all participants. At the end of the exposure assessment period, blood and urine samples were collected at the plant; samples were. fractionated, cryopreserved, and kept frozen in Prague until they were shipped to the appropriate laboratories for specific biomarker analysis. The following biomarkers were analyzed: * polymorphisms in genes involved in BD metabolism (Prague and Burlington); * urinary concentrations of 1-hydroxy-2-(N-acetylcysteinyl)-3-butene and 2-hydroxy-1-(N-acetylcysteinyl)-3-butene (M2 [refers to an isomeric mixture of both forms]) (Amsterdam); * urinary concentrations of 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane (M1) (Amsterdam); * concentrations of the hemoglobin (Hb) adducts N-(1-[hydroxymethyl]-2-propenyl)valine and N-(2-hydroxy-3-butenyl)valine (HBVal [refers to an isomeric mixture of both forms]) (Amsterdam); * concentrations of the Hb adduct N-(2,3,4-trihydroxybutyl)valine (THBVal) (Chapel Hill); * T cell mutations in the hypoxanthine phosphoribosyltransferase (HPRT) gene (autoradiographic assay in Galveston with slide review in Burlington; cloning assay in Leiden with mutational spectra determined in Burlington); and * chromosomal aberrations by the conventional method and by fluorescence in situ hybridization [FISH]), and cytogenetic changes (sister chromatid exchanges [SCEs] (Prague). All assay analysts were blinded to worker and sample identity and remained so until all work in that laboratory had been completed and reported. Assay results were sent to the Biometry Facility in Burlington for statistical analyses. Analysis of questionnaire data revealed that the three exposure groups were balanced with respect to age and years of residence in the district, but the control group had significantly more education than the other two groups and included fewer smokers. Group average BD exposures were 0.023 mg/m3 (0.010 ppm) for the control group, 0.642 mg/m3 (0.290 ppm) for the monomer group, and 1.794 mg/m3 (0.812 ppm) for the polymer group; exposure levels showed considerable variability between and within individuals. Styrene exposures were significantly higher in the polymer group than in the other two groups. We found no statistically significant differences in the distributions of metabolic genotypes over the three exposure groups; genotype frequencies were consistent with those previously reported for this ethnic and national population. Although some specific genotypes were associated with quantitative differences in urinary metabolite concentrations or Hb adduct dose-response characteristics, none indicated a heightened susceptibility to BD. Concentrations of both the M2 and M1 urinary metabolites and both the HBVal and THBVal Hb adducts were significantly correlated with group and individual mean BD exposure levels; the Hb adducts were more strongly correlated than the urinary metabolites. By contrast, no significant relations were observed between BD exposures and HPRT gene mutations (whether determined by the auto-radiographic or the cloning method) or any of the cytogenetic biomarkers (whether determined by the conventional method or FISH analysis). Neither the mutational nor the cytogenetic responses showed any association with genotypes. The molecular spectrum of HPRT mutations in BD-exposed workers showed a high frequency of deletions; but the same result was found in the unexposed control subjects, which suggests that these were not due to BD exposure. This lack of association between BD exposures and genetic effects persisted even when control subjects were excluded from the analyses or when we conducted regression analyses of individual workers exposed to different levels of BD.
Validation and evaluation of biomarkers in workers exposed to benzene in China.
Qu Q, Shore R, Li G … +19 more , Jin X, Chen LC, Cohen B, Melikian AA, Eastmond D, Rappaport S, Li H, Rupa D, Waidyanatha S, Yin S, Yan H, Meng M, Winnik W, Kwok ES, Li Y, Mu R, Xu B, Zhang X, Li K
Res Rep Health Eff Inst · 2003 Jun · PMID 12931845
This study was conducted to validate biomarkers for early detection of benzene exposure and effect in 2 phases. The main purpose of phase 1 was to determine whether these biomarkers could reliably detect differences betw...
This study was conducted to validate biomarkers for early detection of benzene exposure and effect in 2 phases. The main purpose of phase 1 was to determine whether these biomarkers could reliably detect differences between workers with high exposure levels and unexposed subjects, which is the minimal screening criterion for a biomarker assay. Phase 2 of the study mainly focused on evaluating the exposure-response relation, confounding factors, and sensitivities of biomarkers for low benzene exposures. The Chinese occupational population studied had a broad range of benzene exposures. On the day of biological sample collection, exposures ranged from 0.06 to 122 ppm with a median exposure of 3.2 ppm. The median of the 4-week mean benzene exposures was 3.8 ppm, and the median lifetime cumulative exposure was 51.1 ppm-years. Compared with benzene levels in collected samples, toluene levels were relatively high, with a median of 12.6 ppm (mean, 26.3 ppm), but xylene levels were low, with a median of 0.30 ppm (mean, 0.40 ppm). The biomarkers evaluated were urinary metabolites S-phenylmercapturic acid (S-PMA*), trans,trans-muconic acid (t,t-MA), hydroquinone (HQ), catechol (CAT), and phenol; albumin adducts of benzene oxide and 1,4-benzoquinone (BO-Alb and 1,4-BQ-Alb, respectively) in blood; blood cell counts; and chromosomal aberrations. Blood cell counts in this population, including red blood cells (RBCs), white blood cells (WBCs), and neutrophils, decreased significantly with increased exposures but remained in normal ranges. Chromosomal aberration data showed significant increases of chromatid breaks and total chromosomal aberrations in exposed subjects compared with unexposed subjects. Among the urinary metabolites, the levels of S-PMA and t,t-MA were significantly elevated after benzene exposures. Both markers showed significant exposure-response trends even over the exposure range from 0 to 1 ppm. However, HQ, CAT, and phenol showed significant increases only for benzene exposure levels above 5 ppm. Multiple regression analyses of these urinary metabolites on benzene exposure indicated that toluene exposure, smoking status, and cotinine levels had no significant effects on urinary metabolite levels. A time-course study estimated the half-lives of S-PMA, t,t-MA, HQ, CAT, and phenol to be 12.8, 13.7, 12.7, 15.0, and 16.3 hours, respectively. Both BO-Alb and 1,4-BQ-Alb showed strong exposure-response associations with benzene. Regression analyses showed that after adjustment for potential confounding by smoking, there was still a strong association between benzene exposure and these markers. Furthermore, the analyses for correlations among biomarkers revealed that the urinary metabolites correlated substantially with each other. The albumin adducts also correlated well with the urinary biomarkers, especially with S-PMA. BO-Alb and 1,4-BQ adducts also correlated well with each other (r = 0.74). For benzene exposure monitoring, both S-PMA and t,t-MA were judged to be good and sensitive markers, which detected benzene exposures at around 0.1 ppm and 1 ppm, respectively. But S-PMA was clearly superior to t,t-MA as a biomarker for low levels of benzene exposure.
Benzene metabolism in rodents at doses relevant to human exposure from urban air.
Turteltaub KW, Mani C
Res Rep Health Eff Inst · 2003 Feb · PMID 12675491
Benzene is both an environmental pollutant and a component of cigarette smoke, gasoline, and automotive emissions. Although occupational exposure to benzene has been shown to cause blood disorders and cancer in humans, t...
Benzene is both an environmental pollutant and a component of cigarette smoke, gasoline, and automotive emissions. Although occupational exposure to benzene has been shown to cause blood disorders and cancer in humans, the potential health effects resulting from exposure to low levels of benzene are not known. The goals of this project were to determine how well benzene is metabolized and to assess its binding to macromolecules in rodents at doses more closely mimicking human environmental exposure. To determine whether genotoxic metabolites of benzene are produced at environmental exposure levels. various doses of 14C-benzene were given intraperitoneally to male B6C3F1 mice at doses from 5 ng/kg to 500 mg/kg body weight. Samples of urine, plasma, liver, and bone marrow were taken at selected times up to 48 hours after exposure. Individual benzene metabolites in the samples were measured by accelerator mass spectrometry (AMS*). Metabolites were quantified by determining the area under the curve (AUC) for 24 to 48 hours. The major metabolites found in urine were an unidentified radiolabeled metabolite. phenyl sulfate, phenyl glucuronide. and muconic acid (an indicator of muconaldehyde formation). The major metabolites found in plasma, liver, and bone marrow samples were muconic acid and hydroquinone. Only liver showed a dose response for hydroquinone and muconic acid. The kinetics of both DNA and protein adduct formation were assessed over 48 hours at a 14C-benzene dose of 5 microg/kg body weight. A dose-response study was then conducted using 14C-benzene doses from 5 ng/kg to 500 mg/kg body weight in B6C3F1 mice. Adduct levels were determined by AMS in liver and bone marrow. DNA and protein adducts in liver reached maximum levels 30 minutes after benzene administration, whereas those in bone marrow reached maximum levels after six hours. Both protein and DNA adduct AUCs were greater in bone marrow than in liver. Dose-response assessments at both 1 and 12 hours showed that DNA and protein adducts in liver and bone marrow were dose dependent over doses spanning eight orders of magnitude. Consistent with the benzene metabolism data, these data show that reactive forms of benzene were present in liver and bone marrow after exposure to human-relevant benzene levels. Thus, at low doses, benzene was absorbed and metabolized into reactive intermediates capable of binding to DNA and protein. The relation between benzene metabolism and macromolecular binding was examined by comparing benzene macromolecular adduct formation among strains of male mice (B6C3F1, DBA/2, and C57BL/6) and male rats. These animals have been reported to have different metabolic capacities for benzene and also different tumorigenic and cytotoxic responses to benzene exposure. We hypothesized that differences in the capacity to metabolize benzene affect macromolecular adduct formation and that the amount of macromolecular damage is related to benzene's ability to cause cancer and other blood disorders. 14C-benzene was administered intraperitoneally to all rodents (5 microg/kg body weight) and adduct levels were determined by AMS at selected time points up to 48 hours after exposure. AUCs for protein and DNA adducts in bone marrow, the primary target organ for benzene toxicity, decreased in the following order: B6C3F1, DBA/2, C57BL/6, and rats. Similarly, adduct AUCs in liver were greater in B6C3F1 mice than in rats although the trend was less clear for the DBA/2 and C57BL/6 mouse strains. The results of this work are consistent with previously published work showing that the ability to metabolize benzene follows a similar pattern with these animals and is consistent with the tumorigenicity of benzene in mice and rats. Thus, our data suggest that benzene toxicity is related to the ability to produce macromolecular adducts. Preliminary studies were conducted to assess adduct dosimetry after low-dose inhalation of benzene. Inhalation methods were developed to administer a nominal body burden of 5 microg benzene/kg body weight. Then, 14C-benzene was administered to B6C3F1 mice and rats by both intraperitoneal (IP) administration and by inhalation, and DNA and protein adducts in liver and bone marrow were analyzed by AMS. AUCs for adduct levels were greater after IP benzene administration than after inhalation of benzene. Adduct levels were greater in DNA from B6C3F1 mouse bone marrow than in DNA from liver regardless of exposure route. Collectively, these data show that the internally reactive dose was greater when benzene exposure was by IP administration. In summary, the results suggest that benzene is metabolized to reactive forms capable of binding both protein and DNA in target and nontarget organs of rats and mice at doses encountered by humans through environmental exposure. Macromolecular binding was dose-dependent at low doses of benzene and reflected benzene toxicity, based on its carcinogenicity and ability to cause other blood-related disorders. These data are consistent with macromolecular adducts being indicative of benzene exposure and benzene toxicity although much more research is needed to validate this point. Additionally, benzene metabolism varies among species and among strains within a species of rodent. Thus data are needed in humans to understand how to use the rodent data in risk assessment and ultimately to determine whether macromolecular adducts are a useful indicator of exposure and a useful predictor of risk.
A personal particle speciation sampler.
Hering S, Kreisberg N, John W
Res Rep Health Eff Inst · 2003 Feb · PMID 12670062
Fuller understanding of personal exposures to particulate matter with aerodynamic diameters below 2.5 microm (PM2.5*) requires a personal sampler suitable for assaying not only PM2.5 mass but also its major chemical cons...
Fuller understanding of personal exposures to particulate matter with aerodynamic diameters below 2.5 microm (PM2.5*) requires a personal sampler suitable for assaying not only PM2.5 mass but also its major chemical constituents: elemental carbon, organic carbon, sulfates, and nitrates. The goal to measure these constituents simultaneously imposes several constraints on personal sampler design. The aim of this project was to develop a sampler within these constraints that would be suitable for personal monitoring over 8 hours. In addition, with the intent to improve the precision of mass measurements, we investigated offline use of beta attenuation. The personal particle speciation sampler (PPSS) includes an inlet to remove particles larger than 2.5 microm, 2 sampling channels, and a pump with flow control. One channel serves for measuring particle mass and inorganic ions; the other, for measuring organic carbon and elemental carbon. Denuders can be placed in either channel or both channels. A backup filter can be placed on the denuded channel to collect volatilized particulate nitrate. Two prototype PPSS units were built and tested. The results of both laboratory testing of key PPSS components and a limited field study of the prototype in comparison to an AIHL (Air and Industrial Hygiene Laboratory) cyclone-based sampler are reported.
Particle characteristics responsible for effects on human lung epithelial cells.
Aust AE, Ball JC, Hu AA … +5 more , Lighty JS, Smith KR, Straccia AM, Veranth JM, Young WC
Res Rep Health Eff Inst · 2002 Dec · PMID 12578113
Some recent epidemiologic investigations have shown an association between increased incidence of respiratory symptoms and exposure to low levels of particulate matter (PM*) less than 10 microm or less than 2.5 microm in...
Some recent epidemiologic investigations have shown an association between increased incidence of respiratory symptoms and exposure to low levels of particulate matter (PM*) less than 10 microm or less than 2.5 microm in aerodynamic diameter (PM10 and PM2.5, respectively). If particulates are causally involved with respiratory symptoms, it is important to understand which components may be responsible. However, increasing evidence suggests that transition metals present in particles, especially iron, generate reactive oxygen species (ROS) that may be involved in producing some of the observed respiratory symptoms. The hypothesis for this study is twofold: bioavailable transition metals from inhaled airborne particulates catalyze redox reactions in human lung epithelial cells, leading to oxidative stress and increased production of mediators of pulmonary inflammation: and the size, transition metal content, and mineral speciation of particulates affect their ability to cause these effects. This work focused on the relation between physical characteristics of particles (eg, size, bioavailable transition metal content, and mineral speciation) and their ability to generate hydroxyl radicals in cell-free systems and to cause oxidative stress, which results in the synthesis of mediators of pulmonary inflammation in cultured human lung epithelial cells. These relations were studied by comparing size-fractionated, chemically characterized coal fly ash (CFA) produced by combustion of three different coals to obtain milligram quantities of ash. One transition metal, iron, was studied specifically because it is by far the predominant transition metal in CFA. In addition, smaller quantities of particles from gasoline engines, diesel engines, and ambient air were studied. Phosphate buffer soluble fractions from particles from all sources were capable of generating ROS, as measured by production of malondialdehyde (MDA) from 2-deoxyribose. This activity was inhibited over 90% for all particles by the metal chelator N-[5-[3-[(5-aminopentyl)hydroxycarbamoyl]propionamidol-pentyl]-3-[[5-(N-hydroxyacetamido)pentyl]carbamoyl]propionohydroxamic acid (desferrioxamine B, or DF), strongly suggesting that transition metal(s), probably iron, were responsible. Particles from coal or gasoline combustion had greater ability to produce ROS than particles from diesel combustion. Iron was mobilized by citrate (at pH 7.5) from particles of all sources tested; gasoline combustion particles were the only particles not analyzed for iron mobilization because there were not enough particles for the iron mobilization assay. CFA particles were size-fractioned; the amount of iron mobilized by citrate was inversely related to the size of particles and also depended on the source of coal. Iron from the CFA particles was responsible for inducing the iron-storage protein ferritin in cultured human lung epithelial cells (A549 cells). The amount of iron mobilized by citrate was directly proportional to the amount of ferritin induced in the A549 cells. Iron from the CFA was also responsible for inducing the inflammatory mediator interleukin (IL) 8 in A549 cells. Iron existed in several species in the fly ash, but the bioavailable iron was associated with the glassy aluminosilicate fraction, which caused ferritin and IL-8 to be induced in the A549 cells. In crustal dust, another component of urban particulates, iron was associated with oxides and clay but not with aluminosilicates. The crustal dust contained almost no iron that could be mobilized by citrate. Iron could be mobilized from diesel combustion particulates, but at a much lower level than for all other combustion particles. Samples of ambient PM2.5 collected in Salt Lake City over 5-day periods during one month varied widely in the amount of iron that could be mobilized. If bioavailable transition metals (eg, iron) are related to the specific biological responses outlined here, then the potential exists to develop in vitro assays to determine whether particulates of unknown composition and origin can cause effects similar to those observed in this study.
Effect of concentrated ambient particulate matter on blood coagulation parameters in rats.
Nadziejko C, Fang K, Chen LC … +3 more , Cohen B, Karpatkin M, Nadas A
Res Rep Health Eff Inst · 2002 Oct · PMID 12503739
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...
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.
Ozone-induced modulation of airway hyperresponsiveness in guinea pigs.
Schlesinger RB, Cohen M, Gordon T … +5 more , Nadziejko C, Zelikoff JT, Sisco M, Regal JF, Ménache MG
Res Rep Health Eff Inst · 2002 Jun · PMID 12322853
Although acute exposure to ozone (03*) has been shown to influence the severity and prevalence of airway hyperresponsiveness, information has been lacking on effects due to long-term exposure at relatively low exposure c...
Although acute exposure to ozone (03*) has been shown to influence the severity and prevalence of airway hyperresponsiveness, information has been lacking on effects due to long-term exposure at relatively low exposure concentrations. The goals of this study were to determine whether long-term repeated ozone exposures could induce nonspecific hyperresponsiveness in normal, nonatopic (nonsensitized) animals, whether such exposure could exacerbate the preexisting hyperresponsive state in atopic (sensitized) animals, or both. The study was also designed to determine whether gender modulated airway responsiveness related to ozone exposure. Airway responsiveness was measured during and after exposure to 0.1 and 0.3 ppm ozone for 4 hours/day, 4 days/week for 24 weeks in normal, nonsensitized guinea pigs, in guinea pigs sensitized to an allergen (ovalbumin) prior to initiation of ozone exposures, and in animals sensitized concurrently with ozone exposures. Both male and female animals were studied. Ozone exposure did not produce airway hyperresponsiveness in nonsensitized animals. Ozone exposure did exacerbate airway hyperresponsiveness to specific and nonspecific bronchoprovocation in both groups of sensitized animals, and this effect persisted at least 4 weeks after the end of the exposures. Although the overall degree of airway responsiveness did differ between genders (males had more responsive airways than did females), the airway response to ozone exposure did not differ between the two groups. Ozone-induced effects upon airway responsiveness were not associated with the number of pulmonary eosinophils or with any chronic pulmonary inflammatory response. Levels of antigen-specific antibodies increased in sensitized animals, and a significant correlation was observed between airway responsiveness and antibody levels. The results of this study provide support for a role of ambient ozone exposure in exacerbation of airway dysfunction in persons with atopy.
Case-cohort study of styrene exposure and ischemic heart disease.
Matanoski GM, Tao X
Res Rep Health Eff Inst · 2002 May · PMID 12214600
Recent epidemiologic studies have consistently reported increased daily mortalities and hospital admissions associated with exposure to particulate air pollution. Ischemic heart disease (IHD*, International Classificatio...
Recent epidemiologic studies have consistently reported increased daily mortalities and hospital admissions associated with exposure to particulate air pollution. Ischemic heart disease (IHD*, International Classification of Diseases, Eighth Revision [ICD-8], codes 410-414) is among those diseases that contribute in large measure to this excess mortality. Some occupational studies have suggested elevated risk of IHD among workers exposed for short periods to styrene, which can be emitted from fossil fuel combustion, aircraft exhausts, and motor vehicle exhausts. Styrene is found in ambient air at average concentrations of a few micrograms per cubic meter or less but may reach very high concentrations at particular locations and times. Unmeasured aerosols of styrene may also increase population exposures. This case-cohort study explored a possible association and dose-response relation between styrene exposure and risk of acute IHD in an occupational setting. The population under study was 6587 male workers employed between 1943 and 1982 in two US plants manufacturing styrene-butadiene polymers used in synthetic rubber. The study assessed all 498 subjects who died from IHD along with a subcohort of twice that size, 997 subjects, selected as a 15% random sample of the full target cohort. IHD deaths during the study led to some overlap between cases and the subcohort, leaving 1424 unique subjects. Job histories were collected for all subjects. Industrial hygienists and engineers from the industry estimated relative exposures for all jobs. Exposure data were collected for many of the jobs from different sources. For any job with no available exposure measurements, z scores were used to estimate job exposure in each plant from the relative exposure level for that job in similar plants and the measurement distribution parameters of the study plant. Standardized mortality ratio (SMR) analyses were used to examine the overall risk of dying from IHD among study subjects compared with the US general population. A significantly elevated SMR of 1.47 with a 95% confidence interval (95% CI) of 1.17 to 1.77 for chronic IHD was found among black workers who had left the plants. A modification of the Cox proportional hazard regression model was used to control for confounders and examine dose-response relations between styrene exposure and the risk of IHD. Employment time-weighted average (TWA) styrene concentration intensity for the most recent 2 years was found significantly associated with death from acute IHD among active workers with a relative hazard of 3.26 to 6.60, depending on duration of employment. In this analysis, the highest relative hazard of 6.60 (95% CI, 1.78-24.54) was among active workers who had been employed for at least 5 years. The results suggest that the exposure intensity was more important than duration of exposure. On the basis of the dose-response relation established in this study, we estimate that for each 10 microg/m3 increase in ambient styrene, acute IHD mortality might increase 0.4%. At normal ambient styrene levels, the relative risk would be increased, at most, 0.1% compared with no exposure. At certain locations and times, however, ambient styrene could reach levels that would result in a relative hazard for acute IHD mortality as high as 3.386-fold the risk at no exposure.
Airborne carbonyls from motor vehicle emissions in two highway tunnels.
Grosjean D, Grosjean E
Res Rep Health Eff Inst · 2002 Jan · PMID 11954678
Carbonyls (aldehydes and ketones) continue to receive scientific and regulatory attention as toxic air contaminants, mutagens, and carcinogens. Vehicle emissions are a major source of carbonyls in outdoor air, but inform...
Carbonyls (aldehydes and ketones) continue to receive scientific and regulatory attention as toxic air contaminants, mutagens, and carcinogens. Vehicle emissions are a major source of carbonyls in outdoor air, but information about the nature and magnitude of carbonyl emissions by motor vehicles is limited. The objective of this study was to identify speciated carbonyls emitted by motor vehicles under real-world, on-road conditions and to calculate on-road carbonyl emission factors. We collected air samples at the inlet and outlet of two highway tunnels, the Caldecott Tunnel near San Francisco and the Tuscarora Mountain Tunnel in Pennsylvania. At the Caldecott Tunnel, the fleet consisted almost entirely of light-duty (LD) vehicles that used California phase 2 reformulated gasoline. Vehicle count, speed and other parameters relevant to carbonyl emissions were nearly the same from one assessment to the next. At the Tuscarora Mountain Tunnel, the fleet included LD vehicles and heavy-duty (HD) diesel trucks. This part of the study was designed to capture differences in percentage of LD and HD vehicles from one assessment to the next. Air downstream of KI oxidant scrubbers was sampled on silica gel cartridges coated with 2,4-dinitrophenylhydrazine (DNPH). Carbonyls were identified as their DNPH derivatives by liquid chromatography (LC) with detection by diode-array, UV-visible spectroscopy and by atmospheric pressure negative-ion chemical ionization mass spectrometry (MS). About 100 carbonyls were identified. For about 30 of these carbonyls, concentrations were measured at the inlet and outlet of both tunnels. This information was used to calculate on-road carbonyl emission factors for LD vehicles (Caldecott Tunnel) and for the overall fleet (Tuscarora Mountain Tunnel). At the Tuscarora Mountain Tunnel, data for the fleet were used to calculate carbonyl emission factors for LD vehicles and for HD diesel trucks, the majority of which were weight class 7-8 trucks. Carbonyl emission factors at the Caldecott Tunnel were calculated as milligrams of emissions per liter of fuel consumed. Those at the Tuscarora Mountain Tunnel were calculated as milligrams of emissions per distance traveled and then converted to milligrams per liter using the fuel economy reported by Gertler et al (2000) for this tunnel (14.75 km/L for LD vehicles and 3.15 km/L for HD vehicles). At the Caldecott Tunnel, the LD vehicles emission factor was 68.4 mg/L for total measured carbonyls; the ten most abundant carbonyls were, in decreasing order, formaldehyde, acetaldehyde, benzaldehyde, acetone, m-tolualdehyde, p-tolualdehyde, methacrolein, o-tolualdehyde, 2,5-dimethylbenzaldehyde, and crotonaldehyde. At the Tuscarora Mountain Tunnel, the LD emission factor was 94.9 mg/L for total measured carbonyls; the ten most abundant carbonyls were formaldehyde, acetone, acetaldehyde, heptanal, crotonaldehyde, 2-butanone, propanal, acrolein, methacrolein, and benzaldehyde. The weight class HD 7-8 vehicle emission factor at the Tuscarora Mountain Tunnel was 82.1 mg/L for total measured carbonyls; the ten most abundant carbonyls were formaldehyde, acetaldehyde, acetone, crotonaldehyde, m-tolualdehyde, 2-pentanone, a C5 saturated aliphatic carbonyl, 2-butanone, benzaldehyde, and methacrolein. The most abundant carbonyl was formaldehyde, which accounted for 45.4% (Caldecott, LD vehicles), 40.1% (Tuscarora Mountain, LD vehicles), and 25.8% (Tuscarora Mountain, HD vehicles) of total measured carbonyl emissions. The three most abundant carbonyls, formaldehyde, acetaldehyde, and acetone, together accounted for 63.0% (Caldecott, LD vehicles), 76.5% (Tuscarora Mountain, LD vehicles), and 50.5% (Tuscarora Mountain, HD vehicles) of total carbonyl emissions. At the Tuscarora Mountain Tunnel, HD vehicles emitted more unsaturated carbonyls, aromatic carbonyls, and dicarbonyls (as a percentage of total carbonyl emissions) than did LD vehicles. For LD vehicles, less acetone and more aromatic carbonyls (as a percentage of total carbonyl emissions) were emitted at the Caldecott Tunnel than at the Tuscarora Mountain Tunnel. The highway tunnel studies described in the main body of the report also offered an opportunity to examine the role of the sampling substrate, a critical aspect of the carbonyl sampling protocol. The results are described in Appendix A. Co-located samples, one collected using a DNPH-coated silica gel cartridge and the other using a DNPH-coated C18 cartridge, were collected downstream of KI oxidant scrubbers at the inlet and outlet of the Caldecott Tunnel. Statistical comparisons of the concentrations measured for about 30 carbonyls indicated good agreement between silica gel cartridges and C18 cartridges for about 25 carbonyls, including formaldehyde and acetaldehyde. Concentrations of acetone and 2-butanone measured using C18 cartridges were lower than those measured using silica gel cartridges.
Real-world particulate matter and gaseous emissions from motor vehicles in a highway tunnel.
Gertler AW, Gillies JA, Pierson WR … +6 more , Rogers CF, Sagebiel JC, Abu-Allaban M, Coulombe W, Tarnay L, Cahill TA
Res Rep Health Eff Inst · 2002 Jan · PMID 11954677
Recent studies have linked atmospheric particulate matter with human health problems. In many urban areas, mobile sources are a major source of particulate matter (PM) and the dominant source of fine particles or PM2.5 (...
Recent studies have linked atmospheric particulate matter with human health problems. In many urban areas, mobile sources are a major source of particulate matter (PM) and the dominant source of fine particles or PM2.5 (PM smaller than 2.5 pm in aerodynamic diameter). Dynamometer studies have implicated diesel engines as being a significant source of ultrafine particles (< 0.1 microm), which may also exhibit deleterious health impacts. In addition to direct tailpipe emissions, mobile sources contribute to ambient particulate levels by brake and tire wear and by resuspension of particles from pavement. Information about particle emission rates, size distributions, and chemical composition from in-use light-duty (LD) and heavy-duty (HD) vehicles is scarce, especially under real-world operating conditions. To characterize particulate emissions from a limited set of in-use vehicles, we studied on-road emissions from vehicles operating under hot-stabilized conditions, at relatively constant speed, in the Tuscarora Mountain Tunnel along the Pennsylvania Turnpike from May 18 through 23, 1999. There were five specific aims of the study. (1) obtain chemically speciated diesel profiles for the source apportionment of diesel versus other ambient constituents in the air and to determine the chemical species present in real-world diesel emissions; (2) measure particle number and size distribution of chemically speciated particles in the atmosphere; (3) identify, by reference to data in years past, how much change has occurred in diesel exhaust particulate mass; (4) measure particulate emissions from LD gasoline vehicles to determine their contribution to the observed particle levels compared to diesels; and (5) determine changes over time in gas phase emissions by comparing our results with those of previous studies. Comparing the results of this study with our 1992 results, we found that emissions of C8 to C20 hydrocarbons, carbon monoxide (CO), and carbon dioxide (CO2) from HD diesel emissions substantially decreased over the seven-year period. Particulate mass emissions showed a similar trend. Considering a 25-year period, we observed a continued downward trend in HD particulate emissions from approximately 1,100 mg/km in 1974 to 132 mg/km (reported as PM2.5) in this study. The LD particle emission factor was considerably less than the HD value, but given the large fraction of LD vehicles, emissions from this source cannot be ignored. Results of the current study also indicate that both HD and LD vehicles emit ultrafine particles and that these particles are preserved under real-world dilution conditions. Particle number distributions were dominated by ultrafine particles with count mean diameters of 17 to 13 nm depending on fleet composition. These particles appear to be primarily composed of sulfur, indicative of sulfuric acid emission and nucleation. Comparing the 1992 and 1999 HD emission rates, we observed a 48% increase in the NOx/CO2 emissions ratio. This finding supports the assumption that many new-technology diesel engines conserve fuel but increase NOx emissions.
Pathogenomic mechanisms for particulate matter induction of acute lung injury and inflammation in mice.
Leikauf GD, McDowell SA, Wesselkamper SC … +12 more , Miller CR, Hardie WD, Gammon K, Biswas PP, Korfhagen TR, Bachurski CJ, Wiest JS, Willeke K, Bingham E, Leikauf JE, Aronow BJ, Prows DR
Res Rep Health Eff Inst · 2001 Dec · PMID 11954676
To begin identifying genes controlling individual susceptibility to particulate matter, responses of inbred mouse strains exposed to nickel sulfate (NiSO4*) were compared with those of mice exposed to ozone (O3) or polyt...
To begin identifying genes controlling individual susceptibility to particulate matter, responses of inbred mouse strains exposed to nickel sulfate (NiSO4*) were compared with those of mice exposed to ozone (O3) or polytetrafluoroethylene (PTFE). The A strain was sensitive to NiSO4-induced lung injury (quantified by survival time), the C3H/He (C3) strain and several other strains were intermediate in their responses, and the C57BL/6 (B6) strain was resistant. The strains showed a pattern of response similar to the patterns of response to O3 and PTFE. The phenotype of A x B6 offspring (B6AF1) resembled that of the resistant B6 parental strain, with strains exhibiting sensitivity in the order A > C3 > B6 = B6AF1. Pathology was comparable for the A and B6 mice, and exposure to NiSO4 at 15 microg/m3 produced 20% mortality in A mice. Strain sensitivity for the presence of protein or neutrophils in lavage fluid differed from strain sensitivity for survival time, suggesting that they are not causally linked but are controlled by an independent gene or genes. In the B6 strain, exposure to nickel oxide (NiO) by instillation (40 to 1000 nm) or inhalation (50 nm) produced no changes, whereas inhalation of NiSO4 (60 or 250 nm) increased lavage proteins and neutrophils. Complementary DNA (cDNA) microarray analysis with 8,734 sequence-verified clones revealed a temporal pattern of increased oxidative stress, extracellular matrix repair, cell proliferation, and hypoxia, followed by a decrease in surfactant-associated proteins (SPs). Certain expressed sequence tags (ESTs), clustered with known genes, suggest possible coregulation and novel roles in pulmonary injury. Finally, locus number estimation (Wright equation) and a genomewide analysis suggested 5 genes could explain the survival time and identified significant linkage for a quantitative trait locus (QTL) on chromosome 6, Aliq4 (acute lung injury QTL4). Haplotype analysis identified an allelic combination of 5 QTLs that could explain the difference in sensitivity to acute lung injury between parental strains. Positional candidate genes for Aliq4 include aquaporin-1 (Aqp1), SP-B, and transforming growth factor-alpha (TGF-alpha). Transgenic mice expressing TGF-alpha were rescued from NiSO4 injury (that is, they had diminished SP-B loss and increased survival time). These findings suggest that NiSO4-induced acute lung injury is a complex trait controlled by at least 5 genes (all possibly involved in cell proliferation and surfactant function). Future assessment of these susceptibility genes (including evaluations of human synteny and function) could provide valuable insights into individual susceptibility to the adverse effects of particulate matter.
Daily mortality and fine and ultrafine particles in Erfurt, Germany part I: role of particle number and particle mass.
Wichmann HE, Spix C, Tuch T … +5 more , Wölke G, Peters A, Heinrich J, Kreyling WG, Heyder J
Res Rep Health Eff Inst · 2000 Nov · PMID 11918089
Increases in morbidity and mortality have been observed consistently and coherently in association with ambient air pollution. A number of studies on short-term effects have identified ambient particles as a major pollut...
Increases in morbidity and mortality have been observed consistently and coherently in association with ambient air pollution. A number of studies on short-term effects have identified ambient particles as a major pollutant in urban air. This study, conducted in Erfurt, Germany, investigated the association of mortality not only with ambient particles but also with gaseous pollutants and indicators of sources. Part I of this study concentrates on particles. Data were collected prospectively over a 3.5-year period from September 1995 to December 1998. Death certificates were obtained from the local authorities and aggregated to daily time series of total counts and counts for subgroups. In addition to standard data for particle mass with diameters < or = 2.5 microm (PM2.5)* or < or = 10 microm (PM10) from impactors, a mobile aerosol spectrometer (MAS) was used to obtain size-specific number and mass concentration data in six size classes between 0.01 microm and 2.5 microm. Particles smaller than 0.1 microm were labeled ultrafine particles (three size classes), and particles between 0.1 and 2.5 microm were termed fine particles (three size classes). Concentrations of the gases sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) were also measured. The daily average total number concentration was 18,000 particles/cm3 with 88% of particles below 0.1 pm and 58% below 0.03 microm in diameter. The average mass concentration (PM2.5) was 26 microg/m3; of this, 75% of particles were between 0.1 and 0.5 microm in diameter. Other average concentrations were 38 microg/m3 for PM10, 17 microg/m3 for SO2, 36 microg/m3 for NO2, and 600 microg/m3 for CO. Ambient air pollution demonstrated a strong seasonality with maximum concentrations in winter. Across the study period, fine particle mass decreased, whereas ultrafine particle number was unchanged. The proportion of ultrafine particles below 0.03 microm diameter increased compared with the proportion of other particles. During the study, concentrations of SO2 and CO also decreased, whereas the concentration of NO2 remained unchanged. The data were analyzed using Poisson regression techniques with generalized additive modeling (GAM) to allow nonparametric adjustment for the confounders. Both the best single-day lag and the overall association of multiple days fitted by a polynomial distributed lag model were used to assess the lag structure between air pollution and death. Mortality increased in association with level of ambient air pollution after adjustment for season, influenza epidemics, day of week, and weather. In the sensitivity analyses, the results proved stable against changes of the confounder model. We saw comparable associations for ultrafine and fine particles in a distributed lag model where the contribution of the previous 4 to 5 days was considered. Furthermore, the data suggest a somewhat more delayed association of ultrafine particles than of fine particles if single-day lags are considered. The associations tended to be stronger in winter than in summer and at ages below 70 years compared to ages above 70 years. Analysis of the prevalent diseases mentioned on death certificates revealed that the overall association for respiratory diseases was slightly stronger than for cardiovascular diseases. In two-pollutant models, associations of ultrafine and fine particles seemed to be largely independent of each other, and the risk was enhanced if both were considered at the same time. Furthermore, when the associations were summed for the six size classes between 0.01 and 2.5 microm, the overall association was clearly stronger than the associations of the individual size classes alone. Associations were observed for SO2, NO2, and CO with mortality despite low concentrations of these gases. These associations disappeared in two-pollutant models for NO2 and CO, but they remained stable for SO2. The persistence of the SO2 effect was interpreted as artifact, however, because the SO2 concentration was much below levels at which effects are usually expected. Furthermore, the results for SO2 were inconsistent with those from earlier studies conducted in Erfurt. We conclude that both fine particles (represented by particle mass) and ultrafine particles (represented by particle number) showed independent effects on mortality at ambient concentrations. Comparable associations for gaseous pollutants were interpreted as artifacts of collinearity with particles from the same sources.
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