Airway geometry models of children's lungs for use in dosimetry modeling.

Single-path whole-lung and lobar models of the lungs of 11 children between 3 mo and 21 yr of age were developed based on a combination of cast data and published information on distal airway dimensions. The cast data used to generate these models were taken from one of the largest databases of actual measurements in children. The methods used to develop the children's models were based on techniques that have been used to develop adult single-path airway geometry models. Model dimensions for the conducting airways, as well as the estimated dead space, for all children fell within the range of the limited published information. Thus, the method for estimating airway dimensions in adults may be successfully applied to develop estimates of airway dimensions in children. The predicted total lung capacity (TLC) for the older children (aged 8 to 21 yr) fell within or near the range arising from published scaling equations. The assumptions used to generate the gas exchange region for children 8 yr and older produced results that were reasonably consistent with available physiological data. However, these assumptions do not result in a physiologically consistent gas exchange region for children 3 yr of age and younger; also, to maintain physiologically reasonable relationships between dead space and alveolar volume, the models for children 3 yr of age and younger resulted in predicted TLCs well below those predicted using published scaling equations. These discrepancies may be reflective of dysanaptic growth, in which the alveolar region is growing more rapidly than the airways. The results for children 3 yr of age and under suggest the need for a greater understanding of lung development during this critical period. This is particularly important considering the increasing evidence that exposure to pollutants and other toxicants and allergens during the first 2 yr of life may have long-term consequences on respiratory disease outcomes. Our results suggest that the geometry model airway dimensions for all ages are appropriate for use with dosimetry models, but dosimetry modelers need to assess carefully the reasonableness of TLC and functional residual capacity volumes to which airway dimensions are scaled for children 3 yr of age and under.

Airway structure variability in the Long-Evans rat lung.

Mathematical models used to study deposition of inhaled toxicants require morphometric data to represent the tracheobronchial airways of laboratory animals. Because of the difficulty and cost of obtaining detailed measurements, morphometric models are generally based on measurements from a small number of specimens. To determine the degree of interanimal variability among laboratory animals of the same strain and size, lengths and diameters of the same 200 airways were measured in solid casts in each of 10 male Long-Evans rats. Intraanimal variability was substantially greater than interanimal variability for airway lengths and diameters. Intraanimal variability was reduced when the airways were grouped so that airway generations were adjusted for lobar position. The study results suggest that detailed measurements of the conducting airways in a small number of casts with summarization techniques that retain lobar information will provide a less variable estimate of lung geometry than a smaller number of measurements made in several casts.

Functional evidence of persistent airway obstruction in rats following a two-hour inhalation exposure to methyl isocyanate.

Pulmonary function was assessed in male, F344 rats 1,2,4,7, and 13 weeks after a single 2-hr exposure to 0, 3, 10, or 30 ppm methyl isocyanate. No significant changes were observed in the rats exposed to 3 ppm through 13 weeks. Diffusing capacity (DLco), quasistatic lung compliance, and homogeneity of ventilation, as determined by multibreath nitrogen washout, were depressed in the rats exposed to 10 and 30 ppm by 1 week after exposure. None of the rats exposed to 30 ppm survived beyond 1 week. By 13 weeks, dramatic increases in lung volumes were observed in the rats exposed to 10 ppm, while DLco and lung compliance were only mildly affected. However, volume-specific DLco and compliance were depressed in the rats exposed to 10 ppm, suggesting that lung hyperinflation or other compensatory means of increasing lung size occurred in response to the methyl isocyanate-induced lung lesion. This group also exhibited increased expiratory times during tidal breathing and severely impaired distribution of ventilated air. Collectively, these results suggest the development and likely progression of a severe, obstructive airway lesion with associated gas trapping, and the existence of a pronounced concentration-response relationship between 3 and 10 ppm methyl isocyanate exposures.

Distribution of particulate matter and tissue remodeling in the human lung.

We examined the relationship between intrapulmonary particle distribution of carbonaceous and mineral dusts and remodeling of the airways along anatomically distinct airway paths in the lungs of Hispanic males from the central valley of California. Lung autopsy specimens from the Fresno County Coroner's Office were prepared by intratracheal instillation of 2% glutaraldehyde at 30 cm H(2)O pressure. Two distinct airway paths into the apico-posterior and apico-anterior portions of the left upper lung lobe were followed. Tissue samples for histologic analysis were generally taken from the intrapulmonary second, fourth, sixth, and ninth airway generations. Parenchymal tissues beyond the 12th airway generation of each airway path were also analyzed. There was little evidence of visible particle accumulation in the larger conducting airways (generations 2-6), except in bronchial-associated lymphoid tissues and within peribronchial connective tissue. In contrast, terminal and respiratory bronchioles arising from each pathway revealed varying degrees of wall thickening and remodeling. Walls with marked thickening contained moderate to heavy amounts of carbonaceous and mineral dusts. Wall thickening was associated with increases in collagen and interstitial inflammatory cells, including dust-laden macrophages. These changes were significantly greater in first-generation respiratory bronchioles compared to second- and third-generation respiratory bronchioles. These findings suggest that accumulation of carbonaceous and mineral dust in the lungs is significantly affected by lung anatomy with the greatest retention in centers of lung acini. Furthermore, there is significant remodeling of this transitional zone in humans exposed to ambient particulate matter.

Comparative stochastic effects of inhaled alpha- and beta-particle-emitting radionuclides in beagle dogs.

The stochastic effects of inhaled, insoluble particles of alpha- or beta-particle-emitting radionuclides were compared in dogs. Male and female beagle dogs were exposed briefly by nasal inhalation to relatively insoluble aerosols of (239)PuO(2) or (144)Ce in fused aluminosilicate particles (FAP) and observed for cancer for their lifetimes. The initial lung burden and retention of each radionuclide was determined by whole-body counting of the emissions from (144)Ce-(144)Pr- or (169)Yb-labeled (239)PuO(2). Lung doses were calculated for each dog from these data. The lung doses ranged from 0.21 to 1200 Gy for (144)Ce FAP and 1.6 to 58 Gy for (239)PuO(2). Dogs with doses to the lung of about 60 Gy or greater from (144)Ce or about 2 Gy or greater from (239)PuO(2) had an increased incidence of lung carcinomas. In dogs exposed to (144)Ce FAP, three organs were targets for neoplasia: lung, tracheobronchial lymph nodes, and heart. The insoluble FAP carried to the lymph nodes draining the lung delivered high radiation doses to the nodes and adjacent heart, resulting in hemangiosarcomas of these organs. In the lung, high radiation doses induced hemangiosarcomas and carcinosarcomas. At lower doses, carcinomas of various histological patterns were induced in the lung. In dogs exposed to (239)PuO(2), the lung was the sole target organ for neoplasia. Nearly all of these neoplasms were carcinomas of various histological patterns. These results indicated that relatively low doses of alpha-particle radiation can induce pulmonary cancers, but relatively large doses of beta-particle radiation are required. In addition, inhaled beta-particle emitters can also induce cancers in lung-associated lymph nodes and heart at these larger absorbed radiation doses.

Comparative deterministic effects of inhaled, insoluble alpha- and beta-particle-emitting radionuclides in dogs.

This report compares the deterministic effects from an alpha-particle-emitting radionuclide, (239)PuO(2), and a beta-particle emitter, (144)Ce in fused aluminosilicate particles (FAP). The studies were conducted in beagle dogs of both genders exposed by inhalation to aerosols of the radionuclides. The initial lung burdens of (239)Pu and (144)Ce were determined by whole-body counting of the (169)Yb added to the plutonium aerosol during its preparation or the (144)Ce and its progeny (144)Pr. In addition, organ retention data were obtained from parallel serial sacrifice studies with the same aerosols. After exposure, the dogs were observed for health effects over their lifetime. The deterministic effects observed for both of these relatively insoluble aerosols were lymphopenia, fibrosis, atrophy of the lung-associated lymph nodes, and radiation pneumonitis. Due to the longer half-life of plutonium, the lymphopenia was more prolonged and the clinical course of the radiation pneumonitis more chronic than that resulting from cerium. The greater tissue penetration of the beta-particle emissions from the cerium resulted in more uniform dose distribution over the lung and the atria of the heart than from the alpha-particle emissions from plutonium.

Artificial surfactant attenuates hyperoxic lung injury in primates. I. Physiology and biochemistry.

Prolonged exposure to O2 causes diffuse alveolar damage and surfactant dysfunction that contribute to the pathophysiology of hyperoxic lung injury. We hypothesized that exogenous surfactant would improve lung function during O2 exposure in primates. Sixteen healthy male baboons (10-15 kg) were anesthetized and mechanically ventilated for 96 h. The animals received either 100% O2 (n = 6) or 100% O2 plus aerosolized artificial surfactant (Exosurf; n = 5). A third group of animals (n = 5) was ventilated with an inspired fraction of O2 of 0.21 to control for the effects of sedation and mechanical ventilation. Hemodynamic parameters were obtained every 12 h, and ventilation-perfusion distribution (VA/Q) was measured daily using a multiple inert-gas elimination technique. Positive end-expiratory pressure was kept at 2.5 cmH2O and was intermittently raised to 10 cmH2O for 30 min to obtain additional measurements of VA/Q. After the experiments, lungs were obtained for biochemical and histological assessment of injury. O2 exposures altered hemodynamics, progressively worsened VA/Q, altered lung phospholipid composition, and produced severe lung edema. Artificial surfactant therapy significantly increased disaturated phosphatidylcholine in lavage fluid and improved intrapulmonary shunt, arterial PO2, and lung edema. Surfactant also enhanced the shunt-reducing effect of positive end-expiratory pressure. We conclude that an aerosolized protein-free surfactant decreased the progression of pulmonary O2 toxicity in baboons.

Cigarette smoke exposure produces more evidence of emphysema in B6C3F1 mice than in F344 rats.

Cigarette smoke (CS) causes pulmonary emphysema in humans, but results of previous studies on CS-exposed laboratory animals have been equivocal and have not clearly demonstrated progression of the disease. In this study, morphometry and histopathology were used to assess emphysema in the lungs of B6C3F1 mice and Fischer-344 rats. The animals were exposed, whole-body, to CS at a concentration of 250 mg total particulate matter/m3 for 6 h/day, 5 days/week, for either 7 or 13 months. Morphometry included measurements of parenchymal air space enlargement (alveolar septa mean linear intercept [Lm], volume density of alveolar air space [VVair]), and tissue loss (volume density of alveolar septa [VVspt]). In addition, centriacinar intra-alveolar inflammatory cells were counted to assess species differences in the type of inflammatory response associated with CS exposure. In mice, many of the morphometric parameters indicating emphysema differed significantly between CS-exposed and control animals. In CS-exposed rats, only some of the parameters differed significantly from control values. The Lm in both CS-exposed mice and rats was increased at 7 and 13 months, indicating an enlargement of parenchymal air spaces, but the VVair was increased significantly only in CS-exposed mice. The VVspt was decreased at both time points in mice, but not in rats, indicating damage to the structural integrity of parenchyma. Morphologic evidence of tissue destruction in the mice included alveoli that were irregular in size and shape and alveoli with multiple foci of septal discontinuities and isolated septal fragments. Morphometric differences in the mice at 13 months were greater than at 7 months, suggesting a progression of the disease. Inflammatory lesions within the lungs of mice contained significantly more neutrophils than those lesions in rats. These results suggest that B6C3F1 mice are more susceptible than F344-rats to the induction of emphysema by this CS exposure regimen and that in mice the emphysema may be progressive. Furthermore, the type of inflammatory response may be a determining factor for species differences in susceptibility to emphysema induction by CS exposure.

Carcinogenicity of inhaled butadiene diepoxide in female B6C3F1 mice and Sprague-Dawley rats.

Previous studies suggest that the greater sensitivity of mice, compared to rats, to the carcinogenicity of 1,3-butadiene (BD) is linked to higher rates of BD metabolism to butadiene diepoxide (BDO2) by mice than rats. The purpose of this study was to determine the tumorigenicity of BDO2 in mice and rats exposed by inhalation to the same concentrations of the agent. Female B6C3F1 mice and Sprague-Dawley rats, 10-11 weeks old, 56/group, were exposed to 0, 2.5, or 5.0 ppm BDO2, 6 h/day, 5 days/week for 6 weeks. At the end of the BDO2 exposure, 8 animals/group were evaluated for toxicity. The remainder of the exposed rats and mice were held for up to 18 months for observation of tumor development. At the end of the exposure, rats had no biologically significant alteration in standard hematological parameters, but mice had a dose-dependent increase in neutrophils and decrease in lymphocytes. Most of the significant lesions in both species were in the nose, concentrated around the main airflow pathway. Necrosis, inflammation, and squamous metaplasia of the nasal mucosa, as well as atrophy of the turbinates, were all present in animals exposed to 5.0 ppm. In mice, necrosis and inflammation subsided within 6 months, but squamous metaplasia remained. In rats that died after exposure, squamous metaplasia was seen in areas of earlier inflammation and extended beyond those areas with time. The metaplasia was severe enough to restrict and occlude the nasopharyngeal duct. Later, keratinizing squamous-cell carcinomas developed from metaplastic foci in rats, but these were not seen in mice. At the end of 18 months, the only significant increase in neoplasia in the exposed rats was a dose-dependent increase in neoplasms of the nasal mucosa (0/47, 12/48, and 21/48 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). Neoplasia of the nasal mucosa did not increase significantly in the mice. Neoplastic lesions in the mice were observed in reproductive organs, lymph nodes, bone, liver, Harderian gland, pancreas, and lung, but the only significant increase in neoplasms in a single organ in the mice was in the Harderian gland (0/40, 2/42, and 5/36 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). This tumor accounts for the apparent trend toward an increase in total neoplastic lesions in mice as a function of dose (10/40, 7/42, and 16/36 for control, 2.5 ppm, and 5.0 ppm, respectively). These findings indicate that the metabolite of BD, BDO2, is carcinogenic in the upper respiratory tract of rats. An increase in upper respiratory tract tumors was not observed in similarly exposed mice, despite the fact that preliminary studies indicated mice should have received twice the dose to tissue than did the rats. Higher cytosolic activity of detoxication enzymes has been reported in the liver and lung cells of the mouse compared to the rat, and this may account, in part, for the differences in response. The transport of externally administered BDO2, into the cell and through the cytoplasm, might allow detoxication of the molecule before it reaches critical sites on the DNA. The results indicate that the site of formation of the BDO2 is important for tumor induction.

Glutathione peroxidase and glutathione transferase activity in rat lung and liver following cadmium inhalation.

A 2-h inhalation exposure to 4.6 mg Cd/m3 decreased pulmonary total glutathione peroxidase (GSH Px) activity and non-selenium peroxidase (GSH non-Se-Px) activity but had no effect on GSH selenium peroxidase (Se-Px) activity. Seventy-two hours after exposure there was an increase in total GSH Px and GSH Se-Px activity and a decrease in GSH non-Se-Px activity. Exposure to 0.44 mg Cd/m3 for 2 h caused no effect on GSH Se-Px at either 0 or 72 h post exposure, but total GSH Px and GSH non-Se-Px activities were decreased up to 72 h post exposure. Exposure to 4.6 mg Cd/m3 caused an increase in hepatic GSH Se-Px activity 72 h post exposure, but no other significant changes were observed in the liver. Changes in GSH non-Se-Px activity did not relate to changes in GSH transferase (Tr) activity. The data suggest that alterations in GSH Px activity by Cd2+ may be due to changes in GSH non-Se-Px activity and that changes in pulmonary GSH Tr and GSH non-Se-Px activities may not be as closely linked as in the liver.

Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part IX: Changes in the tracheobronchial epithelium, pulmonary acinus, and lung antioxidant enzyme activity.

The effect of ozone on the respiratory system is not confined to a single region or a specific cell type. Ozone-induced injury can occur at all levels of the respiratory system. However, the effects of this oxidant gas throughout the tracheobronchial tree and the lung parenchyma can be highly variable. The doses of ozone delivered to the various regions may also be different, and these differences may have a significant effect on the extent of injury. To examine the effects of chronic exposure to ozone on the lungs, we used a systematic sampling approach to perform morphometric, histochemical, and enzymatic analyses of selected airway generations and pulmonary acini arising from short and long airway paths of the tracheobronchial tree. The objectives of this study were to define compositional, cytochemical, and architectural changes that occur in epithelial cells of the airways and major tissue components of the pulmonary acini after 20 months of exposure to 0.0, 0.12, 0.5, or 1.0 parts per million (ppm)* ozone in male and female F344/N rats. We found in the trachea and bronchi significant alterations in stored secretory product following exposure to ozone, but no changes in epithelial thickness or the volume density of nonciliated cells. The volume density of nonciliated cells was significantly increased in terminal bronchioles arising from a long airway path (caudal region) of the left lung. The predominant change within the pulmonary acini was the extension of bronchiolar epithelium beyond the bronchiole-alveolar duct junction into alveoli. This change was concentration-dependent and site-specific, with ventilatory units arising from a short path (cranial region) of the left lung in male rats being most affected. The antioxidant enzymes superoxide dismutase, glutathione peroxidase, and glutathione S-transferase were significantly elevated in the distal bronchiole to central acinus following 20 months of exposure to 0.5 or 1.0 ppm ozone. Changes in antioxidant enzyme levels were more variable in other airway generations. We conclude that the effects of long-term (20-month) exposure to ozone are dose-dependent and site-specific along the tracheobronchial tree and pulmonary acini of the lungs. With the tissue sampling strategies used in this study, for the first time microdosimetric relations between ozone concentrations and biological changes in precisely delineated regions of the lungs can be defined along the entire lower respiratory tract.

Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part VIII: Morphometric analysis of structural alterations in alveolar regions.

Morphometric techniques were used to examine cellular and tissue changes occurring in male and female rat lungs exposed to ozone for a prolonged time. F344/N rats were exposed to 0.0, 0.12, 0.5, or 1.0 parts per million (ppm)* ozone for six hours per day, five days per week, for 20 months. Changes in cell volume, cell surface ratios, and cellular characteristics were studied in the terminal bronchioles and in the proximal alveolar regions of the lungs. Animals exposed for 20 months to 0.5 or 1.0 ppm ozone demonstrated dramatic increases in the volume of interstitium and epithelium along the alveolar ducts. The thickening of the epithelium was caused by an epithelial metaplasia in which the normal squamous epithelium was modified to a cuboidal epithelium similar, but not identical, to the type found in terminal bronchioles. This bronchiolar epithelial metaplasia was directly related to dose of ozone, and was characterized by differentiated ciliated cells and Clara cells similar to those found in terminal bronchioles; undifferentiated cuboidal cells also were found in the animals exposed to 0.5 and 1.0 ppm ozone. A mild fibrotic response was seen in the animals exposed to 1.0 ppm ozone, with increases in both the interstitial matrix and cellular interstitium. The individual components of the interstitial matrix, including collagen, elastin, basement membrane, and acellular spaces, all were increased. The increase in cellular interstitium was due to an increase in the volume of interstitial fibroblasts. A slight inflammatory response, identified by an increase in alveolar macrophages, was observed in the animals exposed to 1.0 ppm. The terminal bronchioles were less affected than the proximal alveolar region by the ozone exposures, which may indicate a resistance of this tissue to ozone damage. The changes in the terminal bronchioles mainly consisted of a shift in cell type from ciliated to Clara cells in the animals exposed to 1.0 ppm ozone. The bronchiolar epithelial metaplasia observed in the proximal alveolar ducts may indicate that a protective mechanism develops in response to prolonged exposure to high concentrations of ozone.

Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part XIII. A comparison of changes in the tracheobronchial epithelium and pulmonary acinus in male rats at 3 and 20 months.

A limitation of the NTP/HEI Collaborative Ozone Project conducted with F344/N rats at the Battelle Pacific North-west Laboratories in Richland, WA (1991-1993) was that the study used only one time point (20 months) to examine the chronic effects of exposure to ozone. Issues the design of that study could not address were (1) the status of cellular differentiation at earlier time points during the course of ozone exposure; (2) whether changes that appeared to be compensatory after 20 months of exposure were due to ozone, or were aspects of the natural aging process in rats; (3) the inability to define adequately which effects were related specifically to the prolonged duration of exposure; and (4) how and what changes brought about by the natural aging process may have overridden or confounded a clear definition of the effects of exposure to ozone at ambient concentrations (e.g., 0.12 parts per million [ppm]), which are of most concern with long-term exposure to this pollutant. The present study examined the effects of a 3-month exposure to ozone under conditions identical to those of the 20-month NTP/HEI Collaborative Ozone Project. In our facilities at the University of California, Davis, we exposed 42 male F344/N rats to either filtered air or 0.12 or 1.0 ppm ozone. After 3 months of exposure to 1.0 ppm ozone, changes in the distribution of superoxide dismutase (SOD) in the copper-zinc (Cu-Zn) form were shown by a pattern of reduced staining in terminal bronchioles and the centriacinar region; and the manganese (Mn) form of SOD was elevated within the centriacinar region. Further analysis by transmission electron microscopy and immunogold labeling confirmed that Mn SOD was elevated within epithelial type II cells immediately distal to the bronchiole-alveolar duct, junction (BADJ). The trachea, three major bronchi, and a short-length and long-length airway path relative to the trachea were examined by morphometric techniques. The pulmonary acini arising from each of these two paths were also examined morphometrically as a function of distance into the alveolar duct. Cellular changes occurring in each of these anatomical regions after 3 months of exposure were analyzed and compared to the changes noted after the 20-month ozone exposures. We found significant increases in the volume density of nonciliated epithelial cells lining the trachea and caudal bronchi as well as in the proximal and terminal bronchioles of the cranial region at a concentration of 1.0 ppm ozone after both 3 and 20 months of exposure. Remodeling of the centriacinar region, particularly within the cranial region of the lungs after exposure to 1.0 ppm ozone, was statistically significant at both 3 and 20 months. No statistically significant effects were noted following exposure to 0.12 ppm ozone for either 3 or 20 months. An important finding was that age did not influence the effect of ozone on the lungs of rats. We conclude that long-term exposure to ozone, rather than the effects of aging, lead to significant alterations of epithelial cell populations lining the airways and centriacinar region of the lung. Marked cellular changes were noted after exposure to 1.0 ppm ozone, but not to 0.12 ppm.

1,3-butadiene: cancer, mutations, and adducts. Part I: Carcinogenicity of 1,2,3,4-diepoxybutane.

Reports in the literature suggest that one reason for the greater sensitivity of mice to the carcinogenicity of 1,3-butadiene (BD) is that exposed mice metabolize much more of the BD to 1,2,3,4-diepoxybutane (BDO2) than do exposed rats. The purpose of this study was to determine the tumorigenicity of BDO2 in rats and in mice exposed to the same concentration of the agent. Female B6C3F1 mice and Sprague-Dawley rats, 10 to 11 weeks old, 56 per group, were exposed by inhalation to 0, 2.5, or 5.0 ppm BDO2, 6 hours/day, 5 days/week for 6 weeks. Preliminary dosimetry studies in rodents exposed for 6 hours to 12 ppm BDO2 indicated that blood levels would be expected to be approximately 100 and 200 pmol/g at the two exposure concentrations in the rat and twice those levels in the mouse. During the 6-week exposure, the mice at the high exposure level showed signs of labored breathing during the last week, and four mice died. In the others, however, the respiratory symptoms disappeared after exposure ended. Rats showed no clinical signs of toxicity during exposure but developed labored breathing after the end of the exposure leading to the death of 13 rats within 3 months. At the end of the exposure, some animals (8 per group) were evaluated for the acute toxicity resulting from the BDO2 exposure. The remaining exposed rats and mice were held for 18 months for observation of tumor development. At the end of the exposure, rats had no biologically significant alteration in standard hematological parameters, but mice had a dose-dependent increase in neutrophils and decrease in lymphocytes. In both species the significant histopathologic lesions were in the nose, concentrated around the main airflow pathway. Necrosis, inflammation, and squamous metaplasia of the nasal mucosa, as well as atrophy of the turbinates, were all present at the end of exposure to 5.0 ppm. Within 6 months, necrosis and inflammation subsided, but squamous metaplasia remained in the mice. In rats that died after exposure, squamous metaplasia was seen in areas of earlier inflammation and, in other rats, extended beyond those areas with time. The metaplasia was severe enough to restrict and occlude the nasopharyngeal duct. Later, keratinizing squamous cell carcinomas developed from the metaplastic foci in rats but not mice. At the end of 18 months, the only significant increase in neoplasia in the exposed rats was a dose-dependent increase in neoplasms of the nasal mucosa (0/47, 12/48, and 21/48 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). Neoplasia of the nasal mucosa did not increase significantly in the mice; neoplastic lesions in the mice were observed in reproductive organs, lymph nodes, bone, liver, Harderian gland, pancreas, and lung. The only significant increase in neoplasms in a single organ in the mice was in the Harderian gland (0/40, 2/42, and 5/36 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). This tumor accounts for the apparent trend toward an increase in total neoplastic lesions in mice as a function of dose (10/40, 7/42, and 16/36 for control, 2.5 ppm, and 5.0 ppm exposures, respectively). These findings indicate that the metabolite of BD, BDO2, is carcinogenic in the respiratory tract of rats. An increase in respiratory tract tumors was not observed in similarly exposed mice despite the fact that preliminary studies indicated mice should have received twice the dose to tissue compared with the rats. High cytosolic activity of detoxication enzymes in the mouse may account, in part, for the differences in response.

Modeling age-related particle deposition in humans.

Inhalation of airborne material poses a potential health risk to various subpopulations one of which is children. Little is known about the fate of particles in the respiratory tracts of children. Modeling efforts have been limited due largely to the lack of adequate information on lung geometry during growth. Lung morphometry measurements in children and adults between 3 months and 21 years of age were used to create 5-lobe lung geometries. Each lobe had a dichotomous, symmetric branching structure and was structurally different from the other lobes. The lung geometries were used in a multiple-path particle deposition model to calculate particle deposition fractions in different regions, lobes and airway generations of the lungs. Simulated breathing patterns were representative of resting breathing. Age-dependent, semi-empirical expressions of particles losses in the nasal airways, which were based on fits to the available experimental measurements, showed larger nasal deposition in adults than in children. Predicted tracheobronchial deposition patterns were similar among different ages for a given particle size. In the alveolar region, the predicted deposition fraction varied with age such that a clear trend could not be identified. Deposition fraction in a lobe was proportional to the volume of air going to that lobe. Deposition fractions in the lower left and right lobes were similar but higher than those in the other lobes for a given particle diameter. Lobar deposition fraction adjusted for lobar lung volume or lung deposition fraction adjusted for lung volume was found to be a unique property for an individual and presented a means for age-dependent deposition comparisons. The adjusted tracheobronchial and pulmonary deposition fractions were greatest for infants and decreased with age. A similar trend was also observed for deposition fraction per unit area as a function of airway generation. The distribution of particle deposition fraction per unit surface area varied with particle size for an individual, with ultrafine particles being more uniformly distributed throughout the lungs and coarse particles depositing primarily in the first few tracheobronchial airways. The trend of particle deposition with age indicates that children, particularly infants, may be at a greater health risk from exposure to airborne particulate matter and noxious materials all other conditions being equal. The age-dependent predicted deposition fraction pattern per unit area of different size particles has implications in the calculation of inhaled reference concentrations as well as site-specific delivery of drugs and other therapeutic compounds to the lungs of patients.

Radon progeny dosimetry in the rat lung.

Deposition, mucociliary clearance, and dosimetry for the inhalation of radon progeny in the rat lung have been simulated for a variety of inhalation conditions. Computations indicate that the exposure-dose conversion factor for the rat lung is approximately twice as high as the corresponding value for the human lung for the same exposure conditions. However, if typical aerosol characteristics are used for animal inhalation experiments and human indoor exposures, the resulting exposure-dose conversion factors are comparable, thereby suggesting similar lung cancer risks per unit exposure. The predicted relative effects of radon progeny disequilibrium and unattached fractions on bronchial doses agree with results from inhalation experiments with laboratory rats.

Inhalation reference dose (RfDi): an application of interspecies dosimetry modeling for risk assessment of insoluble particles.

Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

Modeling energy deposition and cellular radiation effects in human bronchial epithelium by radon progeny alpha particles.

Energy deposition and cellular radiation effects arising from the interaction of single 218Po and 214Po alpha particles with basal and secretory cell nuclei were simulated for different target cell depths in the bronchial epithelium of human airway generations 2, 4, 6, and 10. To relate the random chord lengths of alpha particle tracks through spherical cell nuclei to the resulting biological endpoints, probabilities per unit track length for different cellular radiation effects as functions of LET were derived from in vitro experiments. The radiobiological data employed in the present study were inactivation and mutation (mutant frequency at the HPRT gene) in V79 Chinese hamster cells and inactivation and transformation in C3H 10T1/2 cells. Based on computed LET spectra and relative frequencies of target cells, probabilities for transformation, mutation, and cell killing in basal and secretory cells were computed for a lifetime exposure of 20 WLM. While predicted transformation probabilities were about two orders of magnitude higher than mutation probabilities, they were still about two orders of magnitude lower than inactivation probabilities. Furthermore transformation probabilities for basal cells are generally higher than those for secretory cells, and 214Po alpha particles are primarily responsible for transformations in bronchial target cells.

A morphometric comparison of the nasopharyngeal airway of laboratory animals and humans.

Solid silicone rubber casts of the nasopharyngeal and laryngeal regions of a human cadaver (child, 3 years old) and a laboratory primate (baboon, 10 years old) were made, and cross-sectional areas were measured in detail. Cross-sectional areas of other species reported in the published literature were used for comparison. In the child's nose cast, the frontal nasal duct (frontonasal duct), which enters the anterior part of the middle meatus, and the sphenoidal recess were almost absent. The ethmoidal turbinates (superior and middle concha) and the maxillary turbinates (inferior concha) were present but were not fully developed. In the baboon nose, the different turbinates were well defined and smooth but of a less complex nature than the child's nose. Of the species compared, the baboon's upper airways had the greatest similarity to the human child's. The present study shows that for the species investigated and for those from the literature, the cross-sectional area increases from the external nares to the maxilloturbinate region (inferior concha). There is a relatively sudden drop in cross-sectional area about halfway through the nose. The present study suggests a functional relationship between nasal structure and cross-sectional area across species.

Increased susceptibility to pentobarbital following mouse cytomegalovirus infection: relative roles of viral-induced interferon and viral infection of the liver.

The purpose of this study was to determine the relative roles of viral-induced interferon (IFN) and viral infection of the liver in mouse cytomegalovirus (MCMV)-induced depression of cytochrome P-450 (cyt P-450) levels and enhancement of pentobarbital-induced sleeping time (PEN-ST). This was done by establishing the temporal relationship among the IFN response, viral infection of the liver, suppression of cyt P-450 levels, and enhancement of PEN-ST, by determining the effect of anti-IFN antibody treatment on all of these responses, and by manipulating factors known to influence viral pathogenesis and host response to virus such as animal age, virulence of the virus, and dose of virus. In general, manipulation of these factors toward increased stimulation of host immune responses resulted in greater depression of cyt P-450. The data are consistent with the hypothesis that some IFN-dependent mechanism may have contributed to the effects of MCMV infection on both cyt P-450 levels and PEN-ST; however, the temporal relationship among the various responses measured following viral infection suggested that the effect of the IFN response may be indirect and due to modulation of other host defense mechanisms. Use of anti-IFN antisera to definitively establish a role for IFN in the effects observed here proved unsuccessful. Effects on PEN-ST and cyt P-450 levels did not appear to be related to the magnitude of infection in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)