Joe L. Mauderly

Health Effects of Organic Aerosols

Carbonaceous aerosol, a major component of particulate matter (PM), gases, and vapors in the atmosphere, has been associated with natural and anthropogenic air pollution, reduced visibility, climate modulation, material and ecosystem damage, and adverse health effects. More recently, epidemiological studies have indicated associations between organic fractions of ambient PM and adverse respiratory and cardiovascular health outcomes. The effects of the non-PM components of the organic aerosol have received less attention because their measurement in the general environment is not mandated. This article summarizes current knowledge of the nature, prevalence, and health effects of organic aerosols encountered in the outdoor environment, identifies key information gaps, and presents a conceptual framework for research priorities for resolving those gaps. The broad, diverse class of air contaminants comprising organic aerosols may be more important to public health than the modest attention given to them. This review focuses on hazard identification and exposure assessment for evaluating risks to public health from ambient organic aerosols. Current knowledge is insufficient to support a quantitative characterization of the aggregate risk from organic air contaminants. Assessments should be done for individual species or mixtures. Efforts should be taken to assemble and evaluate a common set of standard reference materials for both organic speciation and health response assays. A greater standardization of approaches across studies and laboratories would be useful to achieve uniformity in assessing health effects. Multidisciplinary research efforts are needed to improve the current regulatory-driven air quality monitoring networks for epidemiological studies. The limited array of biomarkers linking organic aerosols to health effects needs to be expanded and specific organic compounds or classes that are associated with biological effects in human cells or animal studies need to be tested for better understanding of the exposure-response relationship.

Diesel Exhaust Is a Pulmonary Carcinogen in Rats Exposed Chronically by Inhalation

Male and female F344 rats were exposed 7 hr/day, 5 day/week for up to 30 months to automotive diesel engine exhaust at soot concentrations of 0.35, 3.5, or 7.0 mg/m3 or were sham-exposed to clean air. Rats were terminated at 6-month intervals to measure lung burdens of diesel soot and for histopathology. Other rats either died or were terminated after 30 months of exposure. Lungs were fixed, sectioned into 3-mm slices, and examined by a dissecting microscope to detect tumors. Lesions were stained and examined by light microscopy. Survival and body weight were unaffected by exposure. Focal fibrotic and proliferative lung disease accompanied a progressive accumulation of soot in the lung. The prevalence of lung tumors was significantly increased at the high (13%) and medium (4%) dose levels above the control prevalence (1%). Four tumor types, all of epithelial origin, were observed: adenoma, adenocarcinoma, squamous cyst, and squamous cell carcinoma. Logistic regression modeling demonstrated a significant relationship between tumor prevalence and both exposure concentration and soot lung burden. These results demonstrate that diesel exhaust, inhaled chronically at a high concentration, is a pulmonary carcinogen in the rat.

Comparative Pulmonary Toxicities and Carcinogenicities of Chronically Inhaled Diesel Exhaust and Carbon Black in F344 Rats

Abstract Diesel exhaust (DE) is a known pulmonary carcinogen in rats, and the carcinogenic response is known to require the presence of soot. Many estimates of human lung cancer risk from inhaled DE have been developed from rat bioassay data or from the comparative mutagenic potencies of DE soot extract and known human chemical carcinogens. To explore the importance of the DE soot-associated organic compounds in the lung tumor response of rats, male and female F344 rats were exposed chroni cally to diluted whole DE or aerosolized carbon black (CB) 16 hr/day, 5 days/week at target particle concentrations of 2.5 mg/m3 (LDE, LCB) or 6.5 mg/m3 (HDE, HCB) or to filtered air. The CB served as a surrogate for the elemental carbon matrix of DE soot. Considering both the mass fraction of solvent-extractable matter and its mutagenicity in the Ames Salmonella assay, the mutagenicity in revertants per unit particle mass of the CB was three orders of magnitude less than that of the DE soot. Both DE soot and CB particles accumulated progressively in the lungs of exposed rats, but the rate of accumulation was higher for DE soot. In general, DE and CB caused similar, dose-related, nonneoplastic lesions. CB and DE caused significant, exposure concentration-related increases, of similar magnitudes, in the incidences and prevalences of the same types of malignant and benign lung neoplasms in female rats. The incidences of neoplasms were much lower in males than females, and the mci dences were slightly higher among DE- than CB-exposed males. Survival was shortened in the CB-exposed males, and the short ened survival may have suppressed the expression of carcinoge nicity as measured by crude incidence. Logistic regression mod eling did not demonstrate significant differences between the carcinogenic potencies of CB and DE in either gender. The re sults suggest that the organic fraction of DE may not play an important role in the carcinogenicity of DE in rats.

New approaches for the evaluation of pulmonary toxicity: bronchoalveolar lavage fluid analysis☆

Analysis of bronchoalveolar lavage fluid (BAL) is an effective method of detecting an inflammatory response in the lungs of animals in toxicological studies. Alterations in BAL that are the most sensitive indications of an inflammatory response are an increased content of serum proteins and an influx of neutrophils (PMNs). Elevation of the cytoplasmic enzyme lactate dehydrogenase (LDH) is a useful indicator of cytotoxicity. The pulmonary inflammatory response to particles (either mineral dusts or soot) in the lung includes greatly increased activities of such lysosomal enzymes as beta-glucuronidase and beta-N-acetylglucosaminidase in BAL. Examination of alterations in BAL in rats and mice during chronic exposure to high levels of diluted diesel exhaust revealed that steadily increasing levels of LDH, beta-glucuronidase, and hydroxyproline in BAL correlated better with the development of pulmonary fibrosis than did measures of an inflammatory response (protein, PMNs). Analysis of BAL has proven useful, both for detection of lung injury in toxicological screening tests and for determination of the mechanisms of developing chronic lung disease. Future work shows promise of developing assays for BAL analysis to identify the specific site or type of pulmonary injury present.

Lung toxicity of ambient particulate matter from southeastern U.S. sites with different contributing sources : Relationships between composition and effects

Background Exposure to air pollution and, more specifically, particulate matter (PM) is associated with adverse health effects. However, the specific PM characteristics responsible for biological effects have not been defined. Objectives In this project we examined the composition, sources, and relative toxicity of samples of PM with aerodynamic diameter ≥2.5 μm (PM2.5) collected from sites within the Southeastern Aerosol Research and Characterization (SEARCH) air monitoring network during two seasons. These sites represent four areas with differing sources of PM2.5, including local urban versus regional sources, urban areas with different contributions of transportation and industrial sources, and a site influenced by Gulf of Mexico weather patterns. Methods We collected samples from each site during the winter and summer of 2004 for toxicity testing and for chemical analysis and chemical mass balance–based source apportionment. We also collected PM2.5 downwind of a series of prescribed forest burns. We assessed the toxicity of the samples by instillation into rat lungs and assessed general toxicity, acute cytotoxicity, and inflammation. Statistical dose–response modeling techniques were used to rank the relative toxicity and compare the seasonal differences at each site. Projection-to-latent-surfaces (PLS) techniques examined the relationships among sources, chemical composition, and toxicologic end points. Results and conclusions Urban sites with high contributions from vehicles and industry were most toxic.

Relationship between composition and toxicity of motor vehicle emission samples.

In this study we investigated the statistical relationship between particle and semivolatile organic chemical constituents in gasoline and diesel vehicle exhaust samples, and toxicity as measured by inflammation and tissue damage in rat lungs and mutagenicity in bacteria. Exhaust samples were collected from “normal” and “high-emitting” gasoline and diesel light-duty vehicles. We employed a combination of principal component analysis (PCA) and partial least-squares regression (PLS; also known as projection to latent structures) to evaluate the relationships between chemical composition of vehicle exhaust and toxicity. The PLS analysis revealed the chemical constituents covarying most strongly with toxicity and produced models predicting the relative toxicity of the samples with good accuracy. The specific nitro-polycyclic aromatic hydrocarbons important for mutagenicity were the same chemicals that have been implicated by decades of bioassay-directed fractionation. These chemicals were not related to lung toxicity, which was associated with organic carbon and select organic compounds that are present in lubricating oil. The results demonstrate the utility of the PCA/PLS approach for evaluating composition–response relationships in complex mixture exposures and also provide a starting point for confirming causality and determining the mechanisms of the lung effects.

Response of Rodents to Inhaled Diluted Diesel Exhaust: Biochemical and Cytological Changes in Bronchoalveolar Lavage Fluid and in Lung Tissue

The effect of long-term (24 months) inhalation of diesel exhaust on the bronchoalveolar region of the respiratory tract of rodents was assessed by serial (every 6 months) analysis of bronchoalveolar lavage fluid (BALF) and of lung tissue from F344/Crl rats and CD-1 mice (both sexes) exposed to diesel exhaust diluted to contain 0, 0.35, 3.5, or 7.0 mg soot/m3. The purpose of the study was twofold. One was to assess the potential health effects of inhaling diluted exhaust from light-duty diesel engines. The second was to determine the usefulness of BALF analysis in detecting the early stages in the development of nononcogenic lung disease and differentiating them from the normal repair processes. No biochemical or cytological changes in BALF or in lung tissue were noted in either species exposed to the lowest, and most environmentally relevant, concentration of diesel exhaust. In the two higher levels of exposure, a chronic inflammatory response was measured in both species by dose-dependent increases in inflammatory cells, cytoplasmic and lysosomal enzymes, and protein in BALF. Histologically, after 1 year of exposure, the rats had developed focal areas of fibrosis associated with the deposits of soot, while the mice, despite a higher lung burden of soot than the rats, had only a fine fibrillar thickening of an occasional alveolar septa in the high-level exposure group. Higher increases in BALF beta-glucuronidase activity and in hydroxyproline content accompanied the greater degree of fibrosis in the rat. BALF levels of glutathione (GSH) and glutathione reductase activity increased in a dose-dependent fashion and were higher in mice than in rats. Lung tissue GSH was depleted in a dose-dependent fashion in rats but was slightly increased in mice. This depletion may have played a role in the greater fibrogenic response observed in rats. Other tissue changes in enzymatic activity were small compared to changes observed in BALF. The exposure did not increase the cytochrome P-450 content of the lung in either species. The results suggest that, for the noncarcinogenic health effects reported in this paper, there is a threshold of exposure below which adverse effects were not observed. This threshold was well above environmentally relevant levels of diesel exhaust but may be in the range of some occupational exposures. The analysis of BALF proved a useful adjunct to the chronic toxicity study to quantitate the inflammatory changes accompanying the development of pulmonary disease.

Alterations in particle accumulation and clearance in lungs of rats chronically exposed to diesel exhaust

F344 rats were chronically exposed to diesel exhaust at target soot concentrations of 0 (control, C), 0.35 (low, L), 3.5 (medium, M), and 7.0 (high, H) mg/m3. Accumulated lung burdens of diesel soot were measured after 6, 12, 18, and 24 months of exposure. Parallel measurements of particle deposition and clearance were made to provide insight into the mechanisms of particle accumulation in lungs. The fractional deposition of inhaled 67Ga2O3 particles after 6, 12, 18, and 24 months of exposure and of inhaled 134Cs-fused aluminosilicate particles after 24 months were similar for all groups. Progressive increases in lung burdens of soot particles were observed in M and H exposed rats, reaching levels of 11.5 +/- 0.5 and 20.5 +/- 0.8 mg/lung (mean +/- SE), respectively, after 24 months. Rats in the L group had smaller relative increases in lung burden, reaching levels of 0.60 +/- 0.02 mg/lung after 24 months. Tracheal mucociliary clearance measurements, using 99mTc-macroaggregated albumin deposited in the trachea, showed no changes at anytime. There were statistically significant increases in clearance half-times of inhaled radiolabeled particles of 67Ga2O3 as early as 6 months at the H level and 18 months at the M level; no significant changes were seen at the L level. Rats inhaled fused aluminosilicate particles labeled with 134Cs after 24 months of diesel exhaust exposure to measure long-term components of pulmonary clearance. The long-term clearance half-times were 79 +/- 5, 81 +/- 5, 264 +/- 50, and 240 +/- 50 days (mean +/- SE) for the C, L, M, and H groups, respectively. Differences were significant between the C and both the M and H exposure groups (p less than 0.01). Lung burdens of diesel soot were more than expected at the H and M levels and were also associated with impaired particle clearance while smaller responses were observed in both burdens and clearance at the L level.

Is there evidence for synergy among air pollutants in causing health effects

Background Environmental air pollutants are inhaled as complex mixtures, but the long dominant focus of monitoring and research on individual pollutants has provided modest insight into pollutant interactions that may be important to health. Trends toward managing multiple pollutants to maximize aggregate health gains place increasing value on knowing whether the effects of combinations of pollutants are greater than the sum of the effects of individual pollutants (synergy). Objective We reviewed selected published literature to determine whether synergistic effects of combinations of pollutants on health outcomes have actually been demonstrated. Methods and results We reviewed 36 laboratory studies of combinations of ozone with other pollutants that were reported in the recent U.S. Environmental Protection Agency Ozone Criteria Document. We examined original reports to determine whether the experimental design tested for synergy and whether synergy was demonstrated. Fourteen studies demonstrated synergism, although synergistic, additive, and antagonistic effects were sometimes observed among different outcomes or at different times after exposure. Conclusions Synergisms involving O3 have been demonstrated by laboratory studies of humans and animals. We conclude that the plausibility of synergisms among environmental pollutants has been established, although comparisons are limited, and most involved exposure concentrations much higher than typical of environmental pollutants. Epidemiologic research has limited ability to address the issue explicitly.

Lung Tissue Responses and Sites of Particle Retention Differ between Rats and Cynomolgus Monkeys Exposed Chronically to Diesel Exhaust and Coal Dust

Several chronic inhalation bioassays of poorly soluble, nonfibrous particles have resulted in an increased incidence of lung tumors in rats, no increase in lung tumors in Syrian hamsters, and inconsistent results in mice. These results have raised concerns that rats may be more prone than other species to develop persistent pulmonary epithelial hyperplasia, metaplasia, and tumors in response to the accumulation of inhaled particles. In addition, particle deposition and the rate of particle clearance from the lung differ between rats and primates, as does the anatomy of the centriacinar region. For these reasons, the usefulness of pulmonary carcinogenicity data from rats exposed to high concentrations of particles for quantitatively predicting lung cancer risk in humans exposed to much lower environmental or occupational concentrations has been questioned. The purpose of this investigation was to directly compare the anatomical patterns of particle retention and the lung tissue responses of rats and monkeys exposed chronically to high occupational concentrations of poorly soluble particles. Lung sections from male cynomolgus monkeys and F344 rats exposed 7 hr/day, 5 days/week for 24 months to filtered ambient air, diesel exhaust (2 mg soot/m3), coal dust (2 mg respirable particulate material/m3), or diesel exhaust and coal dust combined (1 mg soot and 1 mg respirable coal dust/m3) were examined histopathologically. The relative volume density of particulate material and the volume percentage of the total particulate material in defined pulmonary compartments were determined morphometrically to assess the relative amount and the anatomic distribution of retained particulate material. In all groups, relatively more particulate material was retained in monkey than in rat lungs. After adjustment for differences between rat and monkey controls, the coal dust- and the combined diesel exhaust and coal dust-exposed monkeys retained more particulate material than the coal dust- and the combined diesel exhaust and coal dust-exposed rats, respectively. There was no significant difference in the relative amount of retained particulate material between diesel exhaust-exposed monkeys and rats. Within each species, the sites of particle retention and lung tissue responses were the same for diesel soot, coal dust, and the combined material. Rats retained a greater portion of the particulate material in lumens of alveolar ducts and alveoli than monkeys. Conversely, monkeys retained a greater portion of the particulate material in the interstitium than rats. Rats, but not monkeys, had significant alveolar epithelial hyperplastic, inflammatory, and septal fibrotic responses to the retained particles. These results suggest that intrapulmonary particle retention patterns and tissue reactions in rats may not be predictive of retention patterns and tissue responses in primates exposed to poorly soluble particles at concentrations representing high occupational exposures.