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J L Mauderly

Publications and source records attributed to J L Mauderly.

At least 55 records · Page 3Linked to original sources
PubMed1989

Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance.

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 burdens of Ga2O3 were measured for 1 y 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 clearance 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.

Administration, Inhalation↗
PubMed1989

Retention patterns for inhaled particles in the lung: comparisons between laboratory animals and humans for chronic exposures.

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.

Aerosols↗
PubMed1989

Relationship between collateral flow resistance and alveolar pores in the aging beagle dog.

Controversy exists over the effect of aging on the alveolar pores of Kohn and the functional relevance of observed changes in alveolar pore structure. We investigated the relationship between collateral resistance (Rcoll), as a measurement of the resistance to collateral flow through collateral channels, and the change in number and size of alveolar pores in the aging beagle dog. Healthy beagle dogs from a closed colony were divided into five groups having mean ages of 3, 6, 9, 12, and 14 yr. Rcoll was measured in anesthetized dogs using a wedged-catheter technique. Following euthanasia, the dogs were necropsied, and the same lung lobe was microdissected along a major intrapulmonary airway, allowing sampling of terminal and respiratory bronchioles from the same airway generation in each dog. Scanning electron microscopy was performed on alveoli adjacent to these bronchioles. There was a significant rise in Rcoll with age. Alveolar pore size and number increased significantly with age, which would be anticipated to reduce Rcoll if the alveolar pores provided a major pathway for collateral ventilation in the dog lung. These findings suggest that the alveolar pores are functionally inoperative for collateral ventilation in the lung at functional residual capacity, possibly because they remain closed at a low lung volume and/or are covered by surfactant.

Aging↗
PubMed1989

Influence of experimental pulmonary emphysema on the toxicological effects from inhaled nitrogen dioxide and diesel exhaust.

This project examined the influence of preexisting, experimentally induced pulmonary emphysema on the adverse health effects in rats of chronic inhalation exposure to either nitrogen dioxide or automotive diesel-engine exhaust. Previous reports indicated that humans with chronic lung disease were among those most severely affected by episodic exposures to high concentrations of airborne toxicants. There were no previous reports comparing the effects of chronic inhalation exposure to components of automotive emissions in emphysematous and normal animals. The hypothesis tested in this project was that rats with preexisting pulmonary emphysema were more susceptible than rats with normal lungs to the adverse effects of the toxicant exposures. Young adult rats were housed continuously in inhalation exposure chambers and exposed seven hours per day, five days per week, for 24 months to nitrogen dioxide at 9.5 parts per million (ppm)2, or to diesel exhaust at 3.5 mg soot/m3, or to clean air as control animals. These concentrations were selected to produce mild, but distinct, effects in rats with normal lungs. Pulmonary emphysema was induced in one-half of the rats by intratracheal instillation of the proteolytic enzyme elastase six weeks before the toxicant exposures began. Health effects were evaluated after 12, 18, and 24 months of exposure. The measurements included respiratory function, clearance of inhaled radiolabeled particles, pulmonary immune responses to instilled antigen, biochemistry and cytology of airway fluid, total lung collagen, histopathology, lung morphometry, and lung burdens of diesel soot. The significance of influences of emphysema and toxicant exposure, and interactions between influences of the two treatments, were evaluated by analysis of variance. The elastase treatment resulted in pulmonary emphysema that was manifested by enlarged alveoli and alveolar ducts, and by ruptured alveolar septa. There was no accompanying inflammation and no alterations of bronchioles. The emphysema persisted throughout the study period, with little evidence of progression. Lung weight was increased, physiological lung volumes were enlarged, lung compliance was increased, and airflow was obstructed. Nitrogen dioxide exposure of normal rats caused mild epithelial hyperplasia and a thickening of the walls of terminal bronchioles, an extension of bronchiolar epithelium into proximal alveoli, and inflammation in proximal alveoli. Lung volume and weight and the lung collagen content were increased. Airway fluid indicators of cell damage and oxidant protective mechanisms were increased. Similar effects of nitrogen dioxide exposure were superimposed over the effects of emphysema in emphysematous nitrogen dioxide-exposed rats. Several parameters were affected similarly by nitrogen dioxide exposure and emphysema (for example, increased lung volume), and the combined effects tended to be additive.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Effects of altered exposure chamber pressure on the breathing pattern of conscious rats in nose-only exposure tubes.

Rats exposed to inhaled toxicants while in plethysmographs having nose or neck seals may breathe against a negative pressure gradient during exposure. Breathing against negative pressure might affect the respiratory pattern and thus, the uptake or deposition of toxicant. The respiration of 10 conscious rats restrained in plethysmographic nose-only inhalation exposure tubes having a neck seal, was measured during breathing against ambient, negative and positive pressures (0 to +/- 7.5 cm H2O). Negative pressure increased respiratory frequency and reduced tidal volume, but minute volume was little changed. The estimated fraction of inspirate reaching the alveoli was reduced and inspiratory flow was increased. The magnitudes of these changes were small at typical exposure pressures, and the magnitudes of their effects on uptake and deposition would be expected to fall within the range of normal intersubject variability. Positive pressure tended to have effects opposite those of negative pressure.

Air Pressure↗
PubMed1988

Distribution of DNA adducts in the respiratory tract of rats exposed to diesel exhaust.

Diesel exhaust, inhaled chronically at high concentrations, was previously found to be a pulmonary carcinogen in rats. The exhaust-induced tumors were located exclusively in the peripheral lung, although all of the respiratory tract tissues were exposed to the exhaust. The purpose of this study was to determine whether there were differences in the level of DNA adducts among the regions of the respiratory tract that paralleled the site of tumors. Groups of male F344/N rats were exposed 7 hr/day, 5 day/week for 12 weeks to diesel engine exhaust at a soot concentration of 10 mg/m3 or were sham-exposed to air. The maxilloturbinates, ethmoturbinates, trachea, left mainstem bronchus (airway generation 1), axial airway (airway generations 2-12), and peripheral lung tissue were dissected from the respiratory tract. DNA was isolated from the dissected samples and analyzed for the presence of adducts using the 32P-postlabeling assay. Chromatographic maps of DNA adducts demonstrated unique patterns of DNA adducts for each of the regions. The highest level of total DNA adducts occurred in peripheral lung tissue (approximately 20 adducts per 10(9) bases). The level of DNA adducts detected in the nasal tissues was about one-fourth to one-fifth that detected in peripheral lung. There were less than three adducts per 10(9) bases in each of the regions of the major conducting airways (i.e., trachea, bronchi, axial airway). In control rats, levels of DNA adducts ranged from one adduct per 10(9) bases (mainstem bronchi, axial airway) to about nine adducts per 10(9) bases (parenchyma). The data from this study indicate that higher levels of total DNA adducts and exhaust-induced adducts (i.e., exposed minus control adducts) were present in tissues where exhaust-induced tumors were located. These data suggest that DNA adduct levels in discrete locations of the respiratory tract may be good measures of the "effective dose" of carcinogenic compounds.

Animals↗
PubMed1988

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.

Animals↗
PubMed1988

Uptake of 19 hydrocarbon vapors inhaled by F344 rats.

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 degrees C) to 1,2,4-trimethylbenzene (BP 169 degrees 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.

Administration, Inhalation↗
PubMed1988

Studies on the ability of rat lung and liver microsomes to facilitate transfer and metabolism of benzo[a]pyrene from diesel particles.

Little is known about the bioavailability of inhaled organic compounds that are associated with particles. It is known that certain particle-associated organic compounds, such as polycyclic aromatic hydrocarbons (PAH) adsorbed on diesel soot particles, are retained in the lung longer than PAH inhaled in pure form. If such particle-associated compounds are available for tissue interaction, their prolonged retention may result in an increased potential for a toxic effect. To determine the factors affecting the bioavailability of particle-associated PAH, we have studied the ability of microsomes to facilitate transfer of benzo[a]pyrene (B[a]P) adsorbed on the surface of diesel exhaust soot particles to the microsomes and the ability of the microsomes to metabolize the transferred B[a]P. Our results indicate that rat lung and liver microsomes were able to facilitate the transfer of small amounts of B[a]P from diesel particles (less than 3%), but only a fraction of the amount transferred (1-2%) was metabolized. Under the same incubation conditions without soot, free B[a]P was extensively metabolized by microsomes, principally to B[a]P-9,10-diol. Lung microsomes were about twice as effective as liver microsomes for the transfer of the B[a]P. The ability to transfer B[a]P to the microsomes was independent of metabolism or the presence of protein, but was related to the lipid content of the microsomal fraction. There was no metabolism of the B[a]P coated on diesel particles as analyzed by high-performance liquid chromatography. These findings suggest that microsomes are able to enhance the slow transfer of only a small amount of B[a]P from diesel particles in a form that can be metabolized. However, over a long period of time, this slow release might be significant.

Adsorption↗
PubMed1988

Cardiopulmonary function of dogs with plutonium-induced chronic lung injury.

Beagle dogs had signs of restrictive lung disease 1 to 5 years after exposure by inhalation to 239PuO2 aerosols. The 239PuO2 aerosols were monodisperse with activity median aerodynamic diameters of 0.75, 1.5, or 3.0 microns. The plutonium particles produced protracted alpha irradiation of the lungs. Ten dogs had specific initial pulmonary burdens (IPB) of 330 to 4,100 kBq of 239PuO2/kg of body mass. The average onset time of clinical signs of lung injury was 3 years after exposure; the average time from the onset of signs until cardiorespiratory function evaluation was 5.5 years. A second group of 10 dogs had IPB of 110 to 2000 kBq of 239Pu/kg of body mass but no signs of lung injury. A third group of 10 dogs, not exposed to 239Pu, were matched for age and sex. Cardiopulmonary function tests were performed. Only the dogs in group I with signs of lung injury had a mild respiratory function disorder consisting of smaller lung volumes, reduced compliance, increased respiratory frequency and minute volume, and reduced carbon monoxide diffusing capacity. Cardiac function of all three groups was similar. These findings indicate that alpha irradiation of the lungs of man could produce restrictive lung disease at long times after initial exposure.

Aerosols↗
PubMed1987

A rapid method for determining soot content of lungs in diesel-exposed rodents.

A rapid optical method for determining the quantity of soot in the lungs of rodents exposed to diluted diesel exhaust has been developed. The method is nondestructive to enzymatic components of the lung, allowing dose and biochemical assays to be done on the same sample. The lung burdens of soot were determined by comparing the extinction of light at 620 nm of lung homogenates from exposed animals to that of lung homogenates containing spiked standards.

Air Pollutants↗
PubMed1987

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.

Adenocarcinoma↗
PubMed1987

The inhalation toxicity of two commercial dyes: solvent yellow 33 and solvent green 3.

The quinoline dye 2-(2'-quinolyl)-1,3-indandione or Solvent Yellow 33 (SY) and the anthraquinone dye 1,4-di-p-toluidinoanthraquinone or Solvent Green 3 (SG) are used in many manufactured products including military smoke grenades. During manufacturing, SY or a combination of both SY and SG can be released into the air, exposing factory workers by inhalation to these dye compounds. The potential inhalation toxicity of these compounds was tested by exposing F344/N rats to different concentrations of SY or SY/SG dye mixture (30:70 w/w) for 6 hr/day, 5 days/week for 4 or 13 weeks. In the 4-week studies, rats were exposed to SY aerosols at average concentrations of 10 +/- 5, 51 +/- 10, or 230 +/- 30 mg/m3 (means +/- SD) or SY/SG aerosols at average concentrations of 11 +/- 5, 49 +/- 11, or 210 +/- 50 mg/m3 (means +/- SD). Rats exposed to the highest concentration of SY or SY/SG had body weights that were approximately 8% or 7% less, respectively, than their controls after exposure. Rats exposed to the highest concentration of SY/SG for 4 weeks also had reduced pulmonary gas exchange efficiency, airflow obstruction, mild pulmonary inflammation, slight Type II pulmonary epithelial cell hyperplasia, and proliferation of vacuolated alveolar macrophages. In the 13-week studies, rats were exposed to SY aerosols at average concentrations of 1.0 +/- 0.2, 10.8 +/- 1.8, or 100 +/- 17 mg/m3 (means +/- SD) or SY/SG aerosols at average concentrations of 1.1 +/- 0.5, 10.2 +/- 3.1, or 101 +/- 23 mg/m3 (means +/- SD). Animals exposed to the highest concentration of SY or SY/SG for 13 weeks had body weights that were approximately 5 or 9% less, respectively, than their controls after exposure and had accumulation of vacuolated alveolar macrophages in lungs. Rats exposed to the highest concentration of SY/SG dye mixture for 13 weeks also had indications of mild pulmonary inflammation and slight Type II pulmonary epithelial cell hyperplasia. Very little SY was found in lungs after any exposures, indicating its clearance from lungs was at a rapid rate. However, significant amounts of the SG component of the SY/SG mixture were detected in lungs after each exposure. Lung clearance half-times of SG from the 13-week exposure were estimated to be approximately 280 days. In summary, neither test material appeared to be highly toxic following inhalation. However, the slightly higher toxicity observed for SY/SG over SY alone is probably related to the longer lung retention of the SG component of the dye mixture.

Administration, Inhalation↗
PubMed1987

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.

Animals↗
PubMed1987

Acute inhalation exposure of azodicarbonamide in the guinea pig.

Humans have been exposed to azodicarbonamide (ADA) by inhalation where bulk quantities of ADA are handled in the workplace. Responses of some workers have led to concern for the potential irritant and sensitizing properties of inhaled ADA. This study examined the effects of inhaling ADA on lung structure and function of guinea pigs during and after an acute exposure. Groups of 20 guinea pigs were exposed to each of 3 concentrations of ADA (19, 58, and 97 mg/m3), plus air as a control, for 1 hr. Pulmonary function was measured before exposure (baseline), during exposure, immediately after exposure and 24 hr after exposure. Dynamic compliance (Cdyn), total pulmonary resistance (RL), tidal volume (VT), respiratory frequency and minute volume were measured. In addition, gross necropsies and histological examinations of respiratory tract tissues were done either immediately following the exposure or 24 hr after exposure. There were no effects of ADA exposure on gross necropsy, histology, Cdyn, or RL. Some significant, concentration-related decreases in VT, respiratory frequency and minute volume were seen. The magnitudes of these changes were small: the largest change was seen in minute volume, amounting to a 24% decrease in the high concentration group. Inhalation exposure of guinea pigs to ADA at concentrations of up to 97 mg/m3 resulted in minor changes in pulmonary function without any changes in lung histology.

Air Pollutants↗
PubMed1987

A method for the continuous measurement of respiration and vapor uptake in rats.

A method for determining the uptake of inhaled vapors in rats is described. The method uses gas chromatographic data to enable calculations of vapor concentration differences upstream and downstream from a rat exposed to the vapor by the nose-only route. Respiratory data are recorded simultaneously. The data can be used to determine the rate of uptake, uptake as a fraction of vapor inhaled and the effects of vapor inhalation on respiration.

Administration, Inhalation↗