Search

In the absence of adequate data exclusively from studies of inhaled particles in people, the results of inhalation studies using laboratory animals are necessary to estimate particle retention in exposed people. To make accurate projections from animal studies and the limited human data, it is necessary to consider species similarities and differences in lung retention and accumulation patterns for inhaled materials. This paper reviews species similarities and differences in pulmonary retention and clearance for inhaled particles, with emphasis on animal species most commonly used in inhalation toxicology research (rats, guinea pigs, dogs, and nonhuman primates). Simulation models for these four species and for humans were used to compare projected lung burdens which would be accumulated during chronic inhalation exposures. These simulation models project an eightfold difference among these species in the lung concentration of particles per gram of lung after a 2-y chronic inhalation exposure to the same aerosol for 8 h d-1, 5 d wk-1. The largest lung accumulation would occur in guinea pigs, the smallest in rats. To reach the same target lung concentration of particles in the lungs of both animals would therefore require about an eightfold difference in air concentration of the exposure material. These comparisons are useful for selecting appropriate laboratory animal species to study as surrogates for humans, for setting aerosol concentrations to use in inhalation studies, and for making approximations of lung burdens that would result from defined exposure scenarios. [ABSTRACT FROM AUTHOR]

Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2 h d-1, 5 d wk-1. Lung clearance was periodically evaluated throughout both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearances of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people. [ABSTRACT FROM AUTHOR]

The risk of bone cancers developing from internally deposited plutonium must be estimated from studies in laboratory animals because no plutonium-induced cancers have been observed in people. Studies of the effects of 226Ra and 239Pu injected into beagle dogs at the University of Utah and 238PuO2 inhaled by beagle dogs at the Inhalation Toxicology Research Institute provide a key link to understanding the longterm effects of inhaled alpha-emitting radionuclides in people. Injected radium and plutonium are rapidly deposited in bone whereas plutonium deposited in lung by inhalation is translocated to bone more slowly, depending on its chemical form. The development of bone cancers is a late occurring effect seen after either injection of plutonium or radium or inhalation of plutonium. The incidence of bone cancers from alpha radiation to the skeletons of dogs was compared to bone cancer incidences in radium dial painters to estimate bone cancer risk from inhaled plutonium in people. A risk factor of 1200 bone cancers/106 rad to skeleton (average dose) was estimated. [ABSTRACT FROM AUTHOR]

Lifespan studies of Beagle dogs that inhaled beta-emitting radionuclides in a relatively insoluble form have been conducted at the Lovelace Inhalation Toxicology Research Institute. These studies were designed to determine the types and locations of radiation-induced tumors as well as the influence of dose protraction on the incidence of such tumors. Although not all these studies are complete, data on organs and cells at risk are available. Histologic tumor types of the lung indicate that numerous cell types are probably at risk after inhalation of beta-emitting radionuclides. Tumors of blood vessels, connective tissue, and pulmonary epithelium have been seen. The numerous cell types involved in tumors of the pulmonary epithelium make it difficult to designate one cell type at risk. The tumors do originate, however, in the terminal airway and alveolar portions of the lung, not the larger airways. Organs other than lung developed tumors through direct irradiation of the tissues. These are tracheobronchial lymph nodes and heart. Neither of these organs has been considered targets for radionuclide-induced tumors. Results from these studies indicate that attention to dose effect relationships in these non-pulmonary tissues may be warranted. [ABSTRACT FROM PUBLISHER]

Ultrafine irregularly-shaped aggregate aerosols of insoluble GaO were generated by heat treatment of vaporized Ga-tetramethylheptanedione. Size characteristics of these aerosols were determined using an electrical aerosol analyser, a diffusion battery and a transmission electron microscope. By varying the experimental conditions, aerosols were produced with volume equivalent diameters ranging from 0.01 to 0.2 μm. The primary particle sizes were between 0.002 to 0.02 μm and the number of primary particles per aggregate ranged from 10–400. Stereoscopic examination revealed that these particles were three dimensional branched chain-like structures. Deposition and retention of inhaled GaO aerosols, with volume equivalent dia. of 0.10 and 0.02 μm, were measured in Beagle dogs. The total deposition was 39±19% and 53±24% of the inhaled 0.10 and 0.02 μm aerosols respectively, while alveolar deposition was 25 and 32% respectively. The pulmonary deposition data agree very well with recent inhalation deposition models. [ABSTRACT FROM PUBLISHER]

Response of Rodents to Inhaled Diluted Diesel Exhaust: Biochemical and Cytological Changes in Bronchoalveolar Lavage Fluid and in Lung Tissue. HENDERSON, R. F., PICKRELL, J. A., JONES, R. K., SUN, J. D., BENSON, J. M., MAUDERLY, J. L., AND MCCLELLAN, R. O. (1988). . 11, 546-567. 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-I mice (both sexes) exposed to diesel exhaust diluted to contain 0, 0.35, 3.5, or 7.0 mg soot/m. 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 ofnonon-cogenic 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 β-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. [ABSTRACT FROM PUBLISHER]

The Uptake of 19 Hydrocarbon Vapors Inhaled by F344 Rats. DAHL, A. R., DAMON, E. G., MAUDERLY, J. L., ROTHENBERG, S. J., SEILER, F. A., AND MCCLELLAN, R. O. (1988). . 10, 262–269. The comparative rates of uptake of 19 hydrocarbon vapors by rats were determined by a dual-column gas chromatograph method. The hydrocarbons ranged in volatility from propylene (BP −47.7°C) to 1,2,4-trimethylbenzene (BP 169°C). Representative compounds from the chemical classes of alkenes, alkynes, straight-chain and branched alkanes, alicyclics, and aromatics were examined. Trends observed included: (1) highly volatile hydrocarbons were less well-absorbed than less volatile hydrocarbons; (2) unsaturated compounds were better absorbed than saturated ones; and (3) branched hydrocarbons were less well-absorbed than unbranched ones. The data indicate that uptake rates among inhaled hydrocarbon vapors may be predicted from the molecular structures and physical properties of the hydrocarbons. [ABSTRACT FROM PUBLISHER]

Alterations in Particle Accumulation and Clearance in Lungs of Rats Chronically Exposed to Diesel Exhaust. WOLFF, R. K., HENDERSON, R. F., SNIPES, M. B., GRIFFITH, W. C., MAUDERLY, J. L., CUDDIHY, R. G., AND MCCLELLAN, R. 0. , 154–166. 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/m 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 GaO particles after 6, 12, 18, and 24 months of exposure and of inhaled Cs-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 (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 Tc-macroaggitated albumin deposited in the trachea, showed no changes at anytime. There were statistically significant increases inclearance half-times of inhaled radiolabeled particles of GaO 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 Cs 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 (± 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 <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. [ABSTRACT FROM PUBLISHER]

Effects of Inhaled Diesel Exhaust on Immune Responses after Lung Immunization. BICE, D. E., MAUDERLY, J. L., JONES, R. K., AND MCCLELLAN, R. O. (1985). 5, 1075–1086. The inhalation of diesel exhaust particles and the accumulation of these particles in the lung-associated lymph nodes could alter the development of immune responses after lung immunization. To study this possibility, Fischer 344 rats and CD-1 mice were exposed to three levels of diesel exhaust (nominal concentration—7000, 3500, or 350 μg particles/m). Chamber controls and exposed animals were immunized by intratracheal instillation of sheep red blood cells (SRBC) after 6, 12,18, and 24 months of exposure. The number of anti-SRBC IgM antibody-forming cells (AFC) in the lung-associated lymph nodes and spleen was evaluated after immunization. The lung-associated lymph nodes from rats and mice exposed to the high levels of diesel exhaust were black with accumulated diesel particles, and the number of lymphoid cells was significantly elevated at each sacrifice time, while rats exposed to the medium level of diesel exhaust also had elevated numbers of cells in these tissues at 12, 18, and 24 months of exposure. The total number of AFC in the lung-associated lymph nodes was significantly elevated ( < 0.05) in rats exposed to medium and high levels of diesel exhaust, but no significant effects were observed in exposed mice. Data expressed as AFC/10 lymphoid cells in rats and mice, and the level of specific IgM, IgG, or IgA antibody in rat sera were not significantly altered. We conclude that the increased cellularity, and the presence of diesel particles in the lung-associated lymph nodes, had a minimal effect on the immune and antigen filtration functions of these tissues. [ABSTRACT FROM PUBLISHER]

New Approaches for the Evaluation of Pulmonary Toxicity: Bronchoalveolar Lavage Fluid Analysis. Henderson, R. F., BENSON, J. M., HAHN, F. F., HOBBS, C. H., JONES, R. K., MAUDERLY, J. L., MCCLELLAN, R. O., AND PICKRELL, J. A., (1985). . 5, 451–458. 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 β-glucuronidase and β--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, β-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 [ABSTRACT FROM PUBLISHER]