Joe L. Mauderly

Context: There have been no animal studies of the health effects of repeated inhalation of mixtures representing downwind pollution from coal combustion. Environmental exposures typically follow atmospheric processing and mixing with pollutants from other sources. Objective: This was the fourth study by the National Environmental Respiratory Center to create a database for responses of animal models to combustion-derived pollutant mixtures, to identify causal pollutants—regardless of source. Methods: F344 and SHR rats and A/J, C57BL/6, and BALB/c mice were exposed 6 h/day 7 days/week for 1 week to 6 months to three concentrations of a mixture simulating key components of “downwind” coal combustion emissions, to the highest concentration filtered to remove particulate matter (PM), or to clean air. Emissions from low-sulfur subbituminous coal were modified to create a mixture recommended by an expert workshop. Sulfur dioxide, nitrogen oxides, and PM were the dominant components. Nonanimal-derived PM mass concentrations of nominally 0, 100, 300, and 1000 µg/m³ were mostly partially neutralized sulfate. Results: Only17 of 270 species-gender-time-outcome comparisons were significantly affected by exposure; some models showed no effects. There was strong evidence that PM participated meaningfully in only three responses. Conclusion: On a total mass or PM mass basis, this mixture was less toxic overall than diesel and gasoline exhausts or wood smoke. The largely sulfate PM contributed to few effects and was the sole cause of none. The study did not allow identification of causal pollutants, but the potential role of NOx in some effects is suggested by the literature.

Ambient air pollution is always encountered as a complex mixture, but past regulatory and research strategies largely focused on single pollutants, pollutant classes, and sources one-at-a-time. There is a trend toward managing air quality in a progressively “multipollutant” manner, with the idealized goal of controlling as many air contaminants as possible in an integrated manner to achieve the greatest total reduction of adverse health and environmental impacts. This commentary considers the current ability of the environmental air pollution exposure and health research communities to provide evidence to inform the development of multipollutant air quality management strategies and assess their effectiveness. The commentary is not a literature review, but a summary of key issues and information gaps, strategies for filling the gaps, and realistic expectations for progress that could be made during the next decade. The greatest need is for researchers and sponsors to address air quality health impacts from a truly multipollutant perspective, and the most limiting current information gap is knowledge of personal exposures of different subpopulations, considering activities and microenvironments. Emphasis is needed on clarifying the roles of a broader range of pollutants and their combinations in a more forward-looking manner; that is not driven by current regulatory structures. Although advances in research tools and outcome data will enhance progress, the greater need is to direct existing capabilities toward strategies aimed at placing into proper context the contributions of multiple pollutants and their combinations to the health burdens, and the relative contributions of pollutants and other factors influencing the same outcomes. The authors conclude that the research community has very limited ability to advise multipollutant air quality management and assess its effectiveness at this time, but that considerable progress can be made in a decade, even at current funding levels, if resources and incentives are shifted appropriately.

Rats were exposed once by inhalation to plutonium-239 dioxide ((239)PuO(2)), resulting in chronic alpha-particle irradiation of the lung, and exposed chronically to cigarette smoke to examine carcinogenic interactions between the two exposures. F344 rats were exposed to (239)PuO(2) to achieve an initial lung burden of 0.5 kBq and then exposed 6 h/day, 5 days/week to cigarette smoke at 100 or 250 mg particulate matter/m(3) for up to 30 months. Exposure to cigarette smoke increased the cumulative radiation dose to lung by slowing the clearance of (239)PuO(2). (239)PuO(2) alone did not affect survival, but the higher cigarette smoke exposure shortened survival in females. Combined exposure to (239)PuO(2) and cigarette smoke acted synergistically to shorten survival in both genders. The combined effects of cigarette smoke and (239)PuO(2) were approximately additive for lung hyperplasia and adenomas but were strongly synergistic for carcinomas. Differences between observed incidences and incidences predicted by survival-adjusted models accounting for increased radiation dose revealed a substantial component of synergy for carcinomas above that attributable to the radiation dose effect. The synergy for malignant lung tumors is consistent with findings from uranium miners and nuclear weapons production workers. These results bolster confidence in the epidemiological findings and have implications for risk assessment.

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.

Gasoline engine emissions are a ubiquitous source of exposure to complex mixtures of particulate matter (PM) and non-PM pollutants; yet their health hazards have received little study in comparison with those of diesel emissions. As a component of the National Environmental Respiratory Center (NERC) multipollutant research program, F344 and SHR rats and A/J, C57BL/6, and BALBc mice were exposed 6 h/day, 7 days/week for 1 week to 6 months to exhaust from 1996 General Motors 4.3-L engines burning national average fuel on a simulated urban operating cycle. Exposure groups included whole exhaust diluted 1:10, 1:15, or 1:90, filtered exhaust at the 1:10 dilution, or clean air controls. Evaluations included organ weight, histopathology, hematology, serum chemistry, bronchoalveolar lavage, cardiac electrophysiology, micronuclei in circulating cells, DNA methylation and oxidative injury, clearance of Pseudomonas aeruginosa from the lung, and development of respiratory allergic responses to ovalbumin. Among the 120 outcome variables, only 20 demonstrated significant exposure effects. Several statistically significant effects appeared isolated and were not supported by related variables. The most coherent and consistent effects were those related to increased red blood cells, interpreted as likely to have resulted from exposure to 13–107 ppm carbon monoxide. Other effects supported by multiple variables included mild lung irritation and depression of oxidant production by alveolar macrophages. The lowest exposure level caused no significant effects. Because only 6 of the 20 significant effects appeared to be substantially reversed by PM filtration, the majority of effects were apparently caused by non-PM components of exhaust.

An animal model of lung carcinogenicity induced by chronic inhalation of mainstream cigarette smoke would be useful for research on carcinogenic mechanisms, smoke composition-response relationships, co-carcinogenicity, and chemoprevention. A study was conducted to determine if chronic whole-body exposures of rats would significantly increase lung tumor incidence. Male and female F344 rats (n = 81 to 178/gender) were exposed whole-body 6 h/day, 5 days/week for up to 30 months to smoke from 1R3 research cigarettes diluted to 100 (LS) or 250 (HS) mg total particulate matter/m³, or sham-exposed to clean air (C). Gross respiratory tract lesions and standard lung and nasal sections were evaluated by light microscopy. A slight reduction of survival suggested that the HS level was at the maximum tolerated dose as commonly defined. Cigarette smoke exposure significantly increased the incidences of non-neoplastic and neoplastic proliferative lung lesions in females, while nonsignificant increases were observed in males. The combined incidence of bronchioloalveolar adenomas and carcinomas in females were: HS = 14%; LS = 6%; and C = 0%. These incidences represented minima because only standard lung sections and gross lesions were evaluated. Mutations in codon 12 of the K-ras gene occurred in 4 of 23 (17%) tumors. Three mutations were G to A transitions and one was a G to T transversion. The incidence of neoplasia of the nasal cavity was significantly increased at the HS, but not the LS level in both males and females (HS = 6%, LS = 0.3%, C = 0.4% for combined genders). These results demonstrate that chronic whole-body exposure of rats to cigarette smoke can induce lung cancer.

It can legitimately be asked whether we need any more research on the health effects of diesel emissions. However, despite a research effort spanning at least 5 decades and the generation of a huge literature, there are still key uncertainties about the health impacts of present and future diesel emissions. This article briefly characterizes current knowledge and information gaps, and then proposes some key issues requiring further research. These issues include the adjuvant effect, the bioactivity of inhaled emissions at realistic doses, the toxicity of aged diesel exhaust particles, the importance of ultrafine particulate emissions, the need to improve our ability to predict the impacts of changes in emissions, and the placement of diesel health risks in context regarding other exposures.