The National Environmental Respiratory Center (NERC) experiment in multi-pollutant air quality health research: II. Comparison of responses to diesel and gasoline engine exhausts, hardwood smoke and simulated downwind coal emissions.

The NERC Program conducted identically designed exposure-response studies of the respiratory and cardiovascular responses of rodents exposed by inhalation for up to 6 months to diesel and gasoline exhausts (DE, GE), wood smoke (WS) and simulated downwind coal emissions (CE). Concentrations of the four combustion-derived mixtures ranged from near upper bound plausible to common occupational and environmental hotspot levels. An "exposure effect" statistic was created to compare the strengths of exposure-response relationships and adjustments were made to minimize false positives among the large number of comparisons. All four exposures caused statistically significant effects. No exposure caused overt illness, neutrophilic lung inflammation, increased circulating micronuclei or histopathology of major organs visible by light microscopy. DE and GE caused the greatest lung cytotoxicity. WS elicited the most responses in lung lavage fluid. All exposures reduced oxidant production by unstimulated alveolar macrophages, but only GE suppressed stimulated macrophages. Only DE retarded clearance of bacteria from the lung. DE before antigen challenge suppressed responses of allergic mice. CE tended to amplify allergic responses regardless of exposure order. GE and DE induced oxidant stress and pro-atherosclerotic responses in aorta; WS and CE had no such effects. No overall ranking of toxicity was plausible. The ranking of exposures by number of significant responses varied among the response models, with each of the four causing the most responses for at least one model. Each exposure could also be deemed most or least toxic depending on the exposure metric used for comparison. The database is available for additional analyses.

The National Environmental Respiratory Center (NERC) experiment in multi-pollutant air quality health research: IV. Vascular effects of repeated inhalation exposure to a mixture of five inorganic gases.

An experiment was conducted to test the hypothesis that a mixture of five inorganic gases could reproduce certain central vascular effects of repeated inhalation exposure of apolipoprotein E-deficient mice to diesel or gasoline engine exhaust. The hypothesis resulted from preceding multiple additive regression tree (MART) analysis of a composition-concentration-response database of mice exposed by inhalation to the exhausts and other complex mixtures. The five gases were the predictors most important to MART models best fitting the vascular responses. Mice on high-fat diet were exposed 6 h/d, 7 d/week for 50 d to clean air or a mixture containing 30.6 ppm CO, 20.5 ppm NO, 1.4 ppm NO2, 0.5 ppm SO2, and 2.0 ppm NH3 in air. The gas concentrations were below the maxima in the preceding studies but in the range of those in exhaust exposure levels that caused significant effects. Five indicators of stress and pro-atherosclerotic responses were measured in aortic tissue. The exposure increased all five response indicators, with the magnitude of effect and statistical significance varying among the indicators and depending on inclusion or exclusion of an apparent outlying control. With the outlier excluded, three responses approximated predicted values and two fell below predictions. The results generally supported evidence that the five gases drove the effects of exhaust, and thus supported the potential of the MART approach for identifying putative causal components of complex mixtures.

Health effects of subchronic inhalation exposure to gasoline engine exhaust.

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.

Health effects of subchronic exposure to environmental levels of hardwood smoke.

Hardwood smoke is a contributor to both ambient and indoor air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center, a series of health assays was conducted on rodents exposed to environmentally relevant levels of hardwood smoke. This article summarizes the study design and exposures, and reports findings on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential. Hardwood smoke was generated from an uncertified wood stove, burning wood of mixed oak species. Animals were exposed to clean air (control) or dilutions of whole emissions based on particulate (30, 100, 300, and 1000 micromg/m3). F344 rats, SHR rats, strain A/J mice, and C57BL/6 mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Effects of exposure on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential were mild. Exposure-related effects included increases in platelets and decreases in blood urea nitrogen and serum alanine aminotransferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Pulmonary histopathology revealed very little accumulation of hardwood smoke particulate matter. Parallel studies demonstrated mild exposure effects on bronchoalveolar lavage parameters and in a mouse model of asthma. In summary, the results reported here show few and only modest health hazards from short-term to subchronic exposures to realistic concentrations of hardwood smoke.

Health effects of subchronic exposure to environmental levels of diesel exhaust.

Diesel exhaust is a public health concern and contributor to both ambient and occupational air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center (NERC), a series of health assays was conducted on rats and mice exposed to environmentally relevant levels of diesel exhaust. This article summarizes the study design and exposures, and reports findings on several general indicators of toxicity and carcinogenic potential. Diesel exhaust was generated from a commonly used 2000 model 5.9-L, 6-cylinder turbo diesel engine operated on a variable-load heavy-duty test cycle burning national average certification fuel. Animals were exposed to clean air (control) or four dilutions of whole emissions based on particulate matter concentration (30, 100, 300, and 1000 microg/m(3)). Male and female F344 rats and A/J mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Exposures were characterized in detail. Effects of exposure on clinical observations, body and organ weights, serum chemistry, hematology, histopathology, bronchoalveolar lavage, and serum clotting factors were mild. Significant exposure-related effects occurring in both male and female rats included decreases in serum cholesterol and clotting Factor VII and slight increases in serum gamma-glutamyl transferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Carcinogenic potential as determined by micronucleated reticulocyte counts and proliferation of adenomas in A/J mice were unaffected by 6 mo of exposure. Parallel studies demonstrated effects on cardiac function and resistance to viral infection; however, the results reported here show few and only modest health hazards from subchronic or shorter exposures to realistic concentrations of contemporary diesel emissions.

Effects of subchronic inhalation exposure of rats to emissions from a diesel engine burning soybean oil-derived biodiesel fuel.

There is increasing interest in diesel fuels derived from plant oils or animal fats ("biodiesel"), but little information on the toxicity of biodiesel emissions other than bacterial mutagenicity. F344 rats were exposed by inhalation 6 h/day, 5 days/wk for 13 wk to 1 of 3 dilutions of emissions from a diesel engine burning 100% soybean oil-derived fuel, or to clean air as controls. Whole emissions were diluted to nominal NO(x) concentrations of 5, 25, or 50 ppm, corresponding to approximately 0.04, 0.2, and 0.5 mg particles/m(3), respectively. Biologically significant, exposure-related effects were limited to the lung, were greater in females than in males, and were observed primarily at the highest exposure level. There was a dose-related increase in the numbers of alveolar macrophages and the numbers of particles in the macrophages, as expected from repeated exposure, but no neutrophil response even at the highest exposure level. The macrophage response was reduced 28 days after cessation of the exposure. Among the high-level females, the group mean lung weight/body weight ratio was increased, and minimal, multifocal bronchiolar metaplasia of alveolar ducts was observed in 4 of 30 rats. Lung weights were not significantly increased, and metaplasia of the alveolar ducts was not observed in males. An increase in particle-laden macrophages was the only exposure-related finding in lungs at the intermediate and low levels, with fewer macrophages and fewer particles per macrophage at the low level. Alveolar histiocytosis was observed in a few rats in both exposed and control groups. There were statistically significant, but minor and not consistently exposure-related, differences in body weight, nonpulmonary organ weights, serum chemistry, and glial fibrillary acidic protein in the brain. There were no significant exposure-related effects on survival, clinical signs, feed consumption, ocular toxicity, hematology, neurohistology, micronuclei in bone marrow, sister chromatid exchanges in peripheral blood lymphocytes, fertility, reproductive toxicity, or teratology. This study demonstrated modest adverse effects at the highest exposure level, and none other than the expected physiological macrophage response to repeated particle exposure at the intermediate level.

Inhaled environmental/occupational irritants and allergens: mechanisms of cardiovascular and systemic responses. Introduction.

The articles in this monograph focus on the mechanisms whereby ambient particulate matter (PM) and co-pollutants deposited in the respiratory tract cause cardiovascular and systemic effects, especially in persons with preexisting conditions such as allergic hyperresponsiveness and pulmonary, cardiac, and vascular diseases. During the past few years, it has become clear that inhaled pollutants cause adverse effects outside the respiratory tract and that these effects may in some cases be more important than respiratory effects. Investigators pursuing traditional approaches to understanding mechanisms of air pollution effects need to be brought together with those outside that community who have expertise in pathogenetic mechanisms by which deposited air pollutants might affect nonrespiratory organs. To this end, a workshop was held and papers were developed from a broad range of scientists having specialized expertise in allergic and cardiovascular physiology. The overall goal of this monograph is to benchmark current thinking and enhance progress toward identifying and understanding the mechanisms by which nonrespiratory health effects occur and, by extension, to facilitate the appropriate management of relationships between air quality and health. This monograph contains a compilation of multidisciplinary research that forms a framework for generating and testing plausible new research hypotheses. Not only will this information stimulate the thinking of researchers, but it will also provide an improved foundation for funding agencies and advisory groups to frame research strategies, programs, and priorities.

Diesel emissions: is more health research still needed?

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.

Animal models for the effect of age on susceptibility to inhaled particulate matter.

Epidemiological findings of associations between ambient particulate matter (PM) and respiratory and cardiovascular mortality and morbidity have fostered increased laboratory research aimed at understanding the key PM components, mechanisms, and dose-response relationships responsible for the effects. Because the health impacts are largely observed in subpopulations having characteristics known or presumed to confer increased susceptibility to PM, there is a need for identifying, developing, and using animal models of these susceptibility factors. Age, during both development and senescence of the cardiorespiratory system and its defenses, is one of the PM susceptibility factors cited frequently. This review is intended as a summary of current knowledge regarding age-related differences in the structure and function of the respiratory and pulmonary vascular systems of humans and animals. Its purpose is to facilitate the selection of appropriate animal models for research on the various facets of potential age-related susceptibility of the human respiratory tract to the effects of inhaled PM. The selection of models is a difficult challenge because no single animal species adequately models the full range of human respiratory anatomy, physiology, and age-related changes. With careful selection among the many species, strains, and comparative ages, however, animals can be selected to model most, if not all, of the individual factors hypothesized to confer increased susceptibility of humans to inhaled PM. The existing information does not provide an adequate basis for selecting models to test all of the current age-related susceptibility hypotheses. However, the information summarized in this report should facilitate the investigator's review of potential models.

Chronic cigarette smoke exposure increases the pulmonary retention and radiation dose of 239Pu inhaled as 239PuO2 by F344 rats.

As a portion of a study to examine how chronic cigarette smoke exposure might alter the risk of lung tumors from inhaled 239puO2 in rats, the effects of smoke exposure on alpha-particle lung dosimetry over the life-span of exposed rats were determined. Male and female rats were exposed to inhaled 239PuO2 alone or in combination with cigarette smoke. Animals exposed to filtered air alone served as controls for the smoke exposure. Whole-body exposure to mainstream smoke diluted to concentrations of either 100 or 250 mg total particulate matter m(-3)(LCS or HCS, respectively) began at 6 wk of age and continued for 6 h d(-1), 5d wk(-1), for 30 mo. A single, pernasal, acute exposure to 239PuO2 was given to all rats (control, LCS and HCS) at 12 wk of age. Exposure to cigarette smoke caused decreased body weight gains in a concentration dependent manner. Lung-to-body weight ratios were increased in smoke-exposed rats. Rats exposed to cigarette smoke before the 239PuO2 exposure deposited less 239Pu in the lung than did controls. Except for male rats exposed to LCS, exposure to smoke retarded the clearance of 239Pu from the lung compared to control rats through study termination at 870 d after 239PuO2 exposure. Radiation doses to lungs were calculated by sex and by exposure group for rats on study for at least 360 d using modeled body weight changes, lung-to-body weight ratios, and standard dosimetric calculations. For both sexes, estimated lifetime radiation doses from the time of 239PuO2 exposure to death were 3.8 Gy, 4.4 Gy, or 6.7 Gy for the control, LCS, or HCS exposure groups, respectively. Assuming an approximately linear dose-response relationship between radiation dose and lung neoplasm incidence, approximate increases of 20% or 80% in tumor incidence over controls would be expected in rats exposed to 239PuO2 and LCS or 239PuO2 and HCS, respectively.

Sites of particle retention and lung tissue responses to chronically inhaled diesel exhaust and coal dust in rats and cynomolgus monkeys.

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 results of several chronic inhalation bioassays of poorly soluble, nonfibrous particles have suggested that rats may be more prone than other rodent species to develop persistent pulmonary epithelial hyperplasia, metaplasia, and tumors in response to the accumulation of inhaled particles. In addition, rats and primates differ in their pulmonary anatomy and rate of particle clearance from the lung. This paper reviews results of recent Lovelace Respiratory Research Institute (Albuquerque, NM) investigations that directly compared 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 obtained from a study conducted at the U.S. National Institute for Occupational Safety and Health and examined histopathologically and morphometrically. Within each species, the sites of particle retention and lung tissue responses were the same for diesel soot, coal dust, and combined material. Rats retained a significantly greater portion of the particulate material in the lumens of alveolar ducts and alveoli than monkeys. Conversely, monkeys retained a significantly 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 anatomic patterns of particle retention and lung tissue reactions in rats may not be predictive of retention patterns and tissue responses in primates that inhale poorly soluble particles at concentrations representing high occupational exposures.

Relevance of particle-induced rat lung tumors for assessing lung carcinogenic hazard and human lung cancer risk.

Rats and other rodents are exposed by inhalation to identify agents that might present hazards for lung cancer in humans exposed by inhalation. In some cases, the results are used in attempts to develop quantitative estimates of human lung cancer risk. This report reviews evidence for the usefulness of the rat for evaluation of lung cancer hazards from inhaled particles. With the exception of nickel sulfate, particulate agents thought to be human lung carcinogens cause lung tumors in rats exposed by inhalation. The rat is more sensitive to carcinogenesis from nonfibrous particles than mice or Syrian hamsters, which have both produced false negatives. However, rats differ from mice and nonhuman primates in both the pattern of particle retention in the lung and alveolar epithelial hyperplastic responses to chronic particle exposure. Present evidence warrants caution in extrapolation from the lung tumor response of rats to inhaled particles to human lung cancer hazard, and there is considerable uncertainty in estimating unit risks for humans from rat data. It seems appropriate to continue using rats in inhalation carcinogenesis assays of inhaled particles, but the upper limit of exposure concentrations must be set carefully to avoid false-positive results. A positive finding in both rats and mice would give greater confidence that an agent presents a carcinogenic hazard to man, and both rats and mice should be used if the agent is a gas or vapor. There is little justification for including Syrian hamsters in assays of the intrapulmonary carcinogenicity of inhaled agents.

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.

Diesel exhaust is not a pulmonary carcinogen in CD-1 mice exposed under conditions carcinogenic to F344 rats.

Differences among laboratory animal species in the pulmonary carcinogenicity of chronic inhalation exposure to diesel exhaust have raised several important interpretive issues. Under similar heavy exposure conditions, it is clear that diesel exhaust is a pulmonary carcinogen in rats, but not in Syrian hamsters. Previous reports give conflicting views of the response of mice, which is presently considered equivocal. This report describes carcinogenicity results from a bioassay of CD-1 mice conducted in parallel with a previously reported bioassay of F344 rats (Mauderly et al. (1987) Fundam. Appl. Toxicol. 9, 208-221). Exposure to whole diesel exhaust 7 hr/day, 5 days/week for 24 months at soot concentrations of 0.35, 3.5, or 7.1 mg/m3 caused accumulations of soot in mouse lungs similar to those in lungs of rats and, like the results from rats, did not significantly affect survival or body weight. In contrast to the dose-related neoplastic response of rats, however, the exposures of mice did not increase the incidence of lung neoplasms. This finding is consistent with other data showing that mice, as well as Syrian hamsters, differ from rats in their lung neoplastic and nonneoplastic responses to heavy, chronic inhalation exposure to diesel exhaust soot and several other particles. Although rodents serve as useful indicators of potential human carcinogenic hazards, it is not yet clear which, if any, rodent species have lung neoplastic responses that are useful for quantitative predictions of human lung cancer risk from chronic inhalation of poorly soluble, respirable particles.

Toxicity of inhaled plutonium dioxide in beagle dogs.

This study was conducted to determine the biological effects of inhaled 238PuO2 over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of 238PuO2 to achieve graded levels of initial lung burden (ILB). The aerosols also contained 169Yb to provide a gamma-ray-emitting label for the 238Pu inhaled by each dog. Excreta were collected periodically over each dog's life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest alpha-particle doses, ranging from 0.16-68 Gy for the lung, 0.08-8.7 Gy for the skeleton and 0.18-19 for the liver. At death all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. Bone tumors found in 93 dogs were the most common cause of death. Lung tumors found in 46 dogs were the second most common cause of death. Liver tumors, which were found in 20 dogs but were the cause of death in only two dogs, occurred later than the tumors in bone and lung. Tumors in these three organs often occurred in the same animal and were competing causes of death. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to 238PuO2.

Comparative pulmonary toxicities and carcinogenicities of chronically inhaled diesel exhaust and carbon black in F344 rats.

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 chronically 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 incidences were slightly higher among DE- than CB-exposed males. Survival was shortened in the CB-exposed males, and the shortened survival may have suppressed the expression of carcinogenicity as measured by crude incidence. Logistic regression modeling did not demonstrate significant differences between the carcinogenic potencies of CB and DE in either gender. The results suggest that the organic fraction of DE may not play an important role in the carcinogenicity of DE in rats.

Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part V: Effects on pulmonary function.

The impact of a 20-month exposure to ozone on the pulmonary function of rats was assessed from a single series of measurements made after exposures were completed. Four to ten male and female F344/N rats per group were exposed six hours per day, five days per week, for 20 months to ozone at 0.12, 0.5, or 1.0 parts per million (ppm), or to clean air as controls. One to three days after the last exposure, the rats were anesthetized using halothane, fitted with oral endotracheal and esophageal catheters, and measured using plethysmographic techniques. The differences between mean values for control and treated rats were tested for significance by multiple comparisons. The values and intersubject variability for more than 30 measured and calculated parameters were similar to those reported previously for rats of similar age. The only consistent exposure-related effect was a small reduction of residual volume measured during slow lung deflation. This trend was observed in most exposure groups, but was most significant in females exposed to ozone at the 0.5 ppm level. Fibrosis and epithelial changes were observed in the terminal bronchiole-alveolar duct region in parallel studies of different rats from the same exposure groups. We hypothesized that these changes stiffened airspace walls and acted to maintain the patency of the air pathway at a lower than normal lung volume during deflation. Overall, the exposures had little impact on the integrated pulmonary function of the lung as measured in anesthetized rats.

Toxicological and epidemiological evidence for health risks from inhaled engine emissions.

Information from toxicological and epidemiological studies of the cancer and noncancer health risks from inhaled diesel engine exhaust (DE) and gasoline engine exhaust (GE) was reviewed. The toxicological database is more extensive for DE than for GE. Animal studies have shown that heavy, chronic exposures to both DE and GE can cause lung pathology and associated physiological effects. Inhaled GE has not been shown to be carcinogenic in animals. Chronically inhaled DE at high concentrations is a pulmonary carcinogen in rats, but the response is questionable in mice and negative in Syrian hamsters. The response in rats is probably not attributable to the DE soot-associated organic compounds, as previously assumed, and the usefulness of the rat data for predicting risk in humans is uncertain. Experimental human exposures to DE show that lung inflammatory and other cellular effects can occur after single exposures, and sparse data suggest that occupational exposures might affect respiratory function and symptoms. Epidemiology suggests that heavy occupational exposures to exhaust probably increase the risks for mortality from both lung cancer and noncancer pulmonary disease. The small magnitudes of the increases in these risks make the studies very sensitive to confounding factors and uncertainties of exposure; thus, it may not be possible to resolve exposure-response relationships conclusively by epidemiology. Our present knowledge suggests that heavy occupational exposures to DE and GE are hazardous but does not allow quantitative estimates of risk with a high degree of certainty.