Biomedical subjects

G L Finch

Publications and source records attributed to G L Finch.

At least 37 records · Page 2Linked to original sources

PubMed1992

Beryllium-induced lung disease in the dog following two exposures to BeO.

We have shown previously that dogs exposed once to aerosols of beryllium oxide (BeO) calcined at 500 or 1000 degrees C developed granulomatous lung lesions as well as Be-specific immune responses in the blood and lung. In this report, we investigate the immunopathologic consequences of exposing dogs twice to aerosols of BeO. Dogs previously exposed to aerosols of 500 or 1000 degrees C calcined BeO to achieve an initial lung burden (ILB) of either 50 or 17 micrograms/kg body wt were exposed a second time to BeO calcined at 500 degrees C, 2.5 years after the first exposure, to achieve an ILB of about 50 micrograms/kg body wt. Immune responses of peripheral blood and lung lymphocytes were measured at 0, 14, 30, 60, 90, 120, 150, 165, 180, and 210 days postexposure (dpe), and dogs were euthanized at 210 dpe. Be-specific immune responses occurred in blood at 30 dpe and again at 150 to 210 dpe. Only sporadic positive responses were seen among lung lymphocytes when cells were cultured in 10% fetal bovine serum. In contrast, samples collected at 165, 180, and 210 dpe and incubated with 10% dog serum showed a large number of positive responses in both blood and lung. Histologic lesions were characterized by perivascular and interstitial infiltrates of lymphocytes and macrophages with progression to patchy granulomatous pneumonia accompanied by focal septal fibrosis. We conclude that Be-induced granulomatous and fibrotic lung lesions are accompanied by Be-specific immune responses within the lung but these changes do not appear to be cumulative if enough time has elapsed between exposures.

Aerosols↗

PubMed1991

Effects of beryllium metal particles on the viability and function of cultured rat alveolar macrophages.

The physicochemical properties of particles influence their in vivo toxicity following deposition in the respiratory tract. To evaluate the relative contributions of mass and surface area to particle-induced toxicity, rat pulmonary alveolar macrophages (PAM) were exposed to four types of particles in vitro. We used three beryllium metal samples: relatively large (Be-II) and relatively small (Be-V) sized fractions of beryllium metal obtained from an aerosol cyclone, and a beryllium metal aerosol generated by laser vaporization of bulk beryllium metal in an argon atmosphere (Be-L). We also used glass beads (GB) as a negative control particle. End points examined included cell viability, determined by trypan blue dye exclusion, and changes in phagocytic ability, measured by counting the number of sheep red blood cells internalized by the PAM. Phagocytic ability was inhibited by exposure to beryllium particles at concentrations that did not cause appreciable cell death. Results describing effects based on the mass concentration of particles in culture medium were transformed by the amount of specific surface area of the particles to permit the expression of toxicity relative to the amount of particle surface per unit volume of culture medium. On a mass basis, the order of particle-related cytotoxicity was Be-L greater than Be-V greater than Be-II greater than GB, and for inhibition of phagocytosis, the order was Be-L approximately Be-V greater than Be-II greater than GB. When analyzed on a specific surface area basis, the cytotoxicity of the different materials became more similar in a fashion that was largely predicted by the amount of surface of the particles administered. However, because differences in specific surface area among the beryllium particle samples did not entirely predict cytotoxicity, we concluded that factors in addition to specific surface area influenced the expression of toxic effects in cultures of PAM exposed to beryllium metal.

Animals↗

PubMed1991

Dosimetry of beryllium in cultured canine pulmonary alveolar macrophages.

This study was designed to determine the dosimetry within macrophages of beryllium compounds administered at sublethal doses. Information on the dosimetry of beryllium within macrophages is required to guide further efforts to isolate and characterize beryllium-containing haptens. Inhalation of beryllium aerosols can cause chronic berylliosis, a progressive, granulomatous fibrosis of the lung. Studies in laboratory animals indicate that alveolar macrophages take up beryllium compounds and participate in a hypersensitivity immune response to beryllium-containing antigen. Beagle dog macrophage cultures were incubated with 7BeSO4 in solution or with suspensions of 7BeO particles that had been calcined at 500 or 1000 degrees C. Beryllium-7 was measured in fractions collected from cultures after successive centrifugation and filtration steps at 2, 6, 20, and 48 h after addition. An insignificant percentage of BeSO4 was taken up by the cells and did not cause cytotoxicity. Maximum BeO uptake occurred within 6 h, was 60 +/- 6% of added BeO, and was independent of BeO calcination temperature or specific surface area. Approximately 22% of 500 degrees C BeO dissolved within 48 h after addition to cell culture, concurrent with 39% cell killing. Dissolved beryllium remained associated with cells until a cytotoxic concentration was reached (2.2 x 10(-5) M, 15 nmol Be/10(6) cells), when the beryllium was released into the medium. There was no significant dissolution of the 1000 degrees C BeO within 48 h, and no significant cell killing. The results indicate that beryllium dissolved from phagocytized BeO was more cytotoxic than soluble beryllium added extracellularly. The data support an interactive mechanism in which phagocytized BeO particles were dissolved, and dissolved beryllium remained associated with the macrophage until a cytotoxic concentration accumulated, whereupon the beryllium was released to the medium and not appreciably taken up by viable cells.

Animals↗

PubMed1990

Clearance, translocation, and excretion of beryllium following acute inhalation of beryllium oxide by beagle dogs.

Beagle dogs inhaled radiolabeled beryllium oxide (7BeO) particles that were calcined at either 500 or 1000 degrees C, resulting in either high (mean of 50 micrograms/kg body wt) or low (mean of 17 micrograms/kg body wt) initial lung burdens (ILBs) of both preparations of BeO. Levels of beryllium in whole body, tissue, and excreta were measured by external gamma-ray counting. Dogs were euthanized in pairs at 8, 32, 64, and 180 days after exposure to determine beryllium distribution in tissues. Beryllium oxide calcined at 1000 degrees C was retained more tenaciously in the lungs (62% of the ILB retained at 180 days after exposure) than BeO calcined at 500 degrees C (14% of the ILB retained at 180 days after exposure). Most of the beryllium that was cleared from the lungs and not excreted was translocated to the tracheobronchial lymph nodes, skeleton, liver, and blood. More beryllium was translocated to the skeleton and liver at 180 days after inhalation of BeO prepared at 500 degrees C than at 1000 degrees C. The predominant mode of excretion at early times after exposure was through the feces, with urinary excretion assuming predominance at later times. These data are important for interpreting the toxic effects of beryllium in the exposed dogs. Furthermore, because little is known concerning the retention and clearance of inhaled beryllium in man, these results provide information that may be used to understand the disposition of beryllium in accidentally exposed humans.

Administration, Inhalation↗

PubMed1990

The acute toxicity of inhaled beryllium metal in rats.

We exposed rats once by nose only for 50 min to a mean concentration of 800 micrograms/m3 of beryllium metal (initial lung burden, 625 micrograms) to characterize the acute toxic effects within the lung. Histological changes within the lung and enzyme changes within bronchoalveolar lavage (BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and 171 days postexposure (dpe). Beryllium metal-exposed rats developed acute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolar fibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesions were replaced by minimal interstitial and intraalveolar fibrosis. Necrotizing inflammation was observed again at 59 dpe which progressed to chronic-active inflammation by 115 dpe. This inflammation worsened progressively, as did alveolar macrophage and epithelial hyperplasia, becoming severe at 171 dpe. Low numbers of diffusely distributed lymphocytes were also present but they were not associated with granulomas as is observed in beryllium-induced disease in man. Throughout the experiment, total numbers of cells were elevated within the BAL samples due primarily to increased numbers of neutrophils. Lymphocytes were not elevated in BAL samples collected from beryllium-exposed rats at any time after exposure. Lactate dehydrogenase (LDH), beta-glucuronidase, and protein levels were elevated in BAL fluid from 3 through 14 dpe but returned to near normal levels by 31 dpe. LDH increased once again at 59 dpe and remained elevated at 171 dpe. beta-Glucuronidase and protein levels were slightly, but not significantly, elevated from 31 through 171 dpe. Results indicate that inhalation of beryllium metal by rats results in severe, acute chemical pneumonitis that is followed by a quiescent period of minimal inflammation and mild fibrosis. Progressive, chronic-active, fibrosing pneumonitis is observed later. Chronic beryllium lung disease of man is an immunologically mediated granulomatous lung disease, whereas beryllium-induced lung lesions in rats appear to be due to direct chemical toxicity and foreign-body-type reactions.

Administration, Inhalation↗

PubMed1989

Determination of the oxide layer thickness on beryllium metal particles.

The hypothesis was tested that beryllium metal particles have a uniformly thick surface coating of beryllium oxide and that smaller particles should have a higher oxide fraction by mass because they have a higher surface to volume ratio. The mass fraction of oxygen, physical density, and specific surface area were determined for size-fractionated samples of respirable beryllium metal particles. The largest particles analyzed (count median diameter 4.6 microns with geometric standard deviation 1.6) contained 7% +/- 1% beryllium oxide by mass; had a physical density of 1.90 +/- 0.02 g/cm3; and had a specific surface area of 4.0 +/- 0.3 m2/g. The smallest particles analyzed (count median diameter 0.4 micron with geometric standard deviation 1.8) contained 31% +/- 3% beryllium oxide by mass; had a physical density of 2.00 +/- 0.17 g/cm3; and had a specific surface area of 20.8 +/- 2.1 m2/g. These shifts in density and oxide content with size and surface area are consistent with a beryllium metal core of density 1.84 +/- 0.02 g/cm3 (1.848 g/cm3 is theoretical); a beryllium oxide layer of density of 2.53 +/- 0.16 g/cm3 (3.025 g/cm3 is the perfect crystalline density); and an oxide layer thickness of 49 +/- 4 A for all particle sizes. These results indicate that the inhalation toxicity of beryllium metal particles may be similar to that of beryllium oxide formed at low temperatures.

Berylliosis↗

PubMed1989

The induction of chromosome damage in CHO cells by beryllium and radiation given alone and in combination.

Studies were conducted to determine the effects of BeSO4 or X rays, alone and in combination, on cell cycle kinetics, cell killing, and the production of chromosome aberrations in Chinese hamster ovary (CHO) cells. The concentration of BeSO4 required to kill 50% of CHO cells exposed to BeSO4 for 20 h was determined to be 1.1 mM with 95% confidence intervals of 0.72 to 1.8 mM. During the last 2 h of the 20-h beryllium treatment (0.2 and 1.0 mM), cells were exposed to 0.0, 1.0, or 2.0 Gy of X rays. Exposure to either BeSO4 or X rays produced a change in cell cycle kinetics which resulted in an accumulation of cells in the G2/M stage of the cell cycle. However, combined exposure to both agents resulted in a block similar to that observed following exposure to X rays only. The background level of chromosome damage was 0.05 +/- 0.015 aberrations/cell in the CHO cells. Seven hours after the end of exposure to 0.2 and 1.0 mM beryllium, 0.03 +/- 0.003 and 0.09 +/- 0.02 aberrations/cell, respectively, were observed. The data for chromosome aberrations following X-ray exposure were fitted to a linear model with a coefficient of 0.14 +/- 0.01 aberrations/cell/Gy. When beryllium was combined with the X-ray exposure the interactive response was predicted by a multiplicative model and was significantly higher (P less than 0.05) than predicted by an additive model. The influence of time after radiation exposure on the interaction between beryllium and X rays was also determined. No interaction between beryllium and X-ray exposure in the induction of chromosome-type aberrations (P greater than 0.05) was detected. The frequency of chromatid-type exchanges and total aberrations was significantly higher (P less than 0.05) in the radiation plus beryllium-exposed cells when compared to cells exposed to X rays only, at both 9 and 12 h after X-ray exposure. These data suggest that the multiplicative interaction may be limited to cells in the S and G2 stages of the cell cycle.

Animals↗

PubMed1989

A canine model of beryllium-induced granulomatous lung disease.

Groups of beagle dogs were exposed by inhalation to attain either low or high initial lung burdens (ILB) of BeO calcined at 500 degrees or 1000 degrees C. Dogs were killed at 8, 32, 64, 180, and 365 days after exposure for evaluation of beryllium tissue burdens and histopathologic examination. Histologic lesions were characterized by perivascular and peribronchiolar infiltrates of lymphocytes and macrophages 8 days after exposure. These lesions progressed to distinct microgranulomas accompanied by patchy granulomatous pneumonia. Lesions were more severe in dogs exposed to 500 degrees C BeO. Additional dogs were sampled by bronchoalveolar lavage at 3, 6, 7, 11, 15, 18, and 22 months after exposure for characterization of lung cytology and lung immune responses. Lymphocyte percentages and numbers were increased in lavage samples 3 months after exposure in dogs with both the high and low ILB of 500 degrees C. Values for both parameters decreased rapidly thereafter. Dogs with either low or high ILB of 1000 degrees C-treated BeO displayed negligible to low and variable changes in both lymphocyte percentages and numbers. In vitro lymphocyte stimulation by beryllium was increased 180 and 210 days after exposure in dogs with the high ILB 500 degrees C BeO only. A marked degree of individual variation in both histologic lesions and lymphocyte responses among dogs was noted. Less soluble 1000 degrees C-treated BeO was retained in the lung longer than the more soluble 500 degrees C-treated material that was cleared almost entirely by 1 year after exposure. Because these changes are similar to those reported in humans with chronic beryllium disease, these data suggest that the beagle represents a good model to study histologic and immunologic aspects of this disease syndrome.

Aerosols↗

PubMed1988

The effect of beryllium compound solubility on in vitro canine alveolar macrophage cytotoxicity.

Pulmonary alveolar macrophage cells (PAM), obtained by bronchopulmonary lavage of Beagle dogs, were exposed in vitro to beryllium oxide (BeO) particles calcined at either 500 or 1000 degrees C or to beryllium sulfate (BeSO4). Cell viability was determined by trypan blue dye exclusion after 20 h in culture. The most toxic material tested was BeSO4, followed by BeO calcined at 500 degrees C, then BeO calcined at 1000 degrees C. An in vitro dissolution technique was used to measure the relative solubility of the BeO particles. The BeO prepared at 500 degrees C exhibited greater solubility compared with BeO prepared at 1000 degrees C. This study extends previous work by examining the effects of beryllium compounds on canine PAM, and by relating PAM cytotoxicity with measured values of beryllium compound solubility.

Animals↗

PubMed1987

The pulmonary effects and clearance of intratracheally instilled Ni3S2 and TiO2 in mice.

The effects and clearance of intratracheally instilled nickel subsulfide (Ni3S2) and titanium dioxide (TiO2) were compared. Instilled Ni3S2 was acutely toxic to mice. Blood was recovered from the lungs during lavage, pulmonary polymorphonuclear leukocyte cell levels were increased, body weights decreased, and mice appeared clinically sick. These effects were in contrast to TiO2-instilled animals, which appeared similar to phosphate-buffered saline-instilled controls. The clearance of instilled particles from the lungs was examined for both Ni3S2- and TiO2-exposed mice. Particles were rapidly cleared to the gastrointestinal (GI) tract within 15 min; this clearance was nonspecific for Ni or Ti and appeared to be due to the coughing reflex. Significantly less Ni was present compared with TiO2 in mouse lungs at 3 and 7 days postexposure (P less than 0.05), with halflifes for the later clearance phase of 119 and 462 hr, respectively. Much of the early Ni lung burden was cleared to the GI tract, and Ni levels in the kidney and blood peaked at 1 hr. Longer-term Ni clearance rate constants were similar for lung, kidney, and blood and were consistent with the hypothesis that 63Ni was first solubilized in the lung then transported through the blood.

Animals↗

PubMed1987

In vitro interactions between pulmonary macrophages and respirable particles.

Pulmonary alveolar macrophage cells (PAM) are an important component of the pulmonary response to particles deposited in the deep lung. To more fully characterize the interactions between macrophages and particulate materials, a correlative light and electron microscopic technique was developed that allowed light microscopic identification of individual cell viability after in vitro particle exposure, followed by scanning and transmission electron microscopic analyses of specific PAM, including surface morphology, X-ray microanalytic evaluation of particle content, and internal cellular structure. Individual cell viability, particle content, and morphologic alterations were evaluated for three particle types: Ni3S2, TiO2, and glass beads. Cell death and stages of cell disruption including bleb cluster formation, loss of surface features, formation of membrane tears and holes, and cell degranulation correlated with Ni3S2 and TiO2 content. Glass beads were not associated with cell disruption or viability reduction. Correlative microscopic techniques were essential in describing particle-dependent effects on an individual cell basis.

Animals↗

PubMed1987

Low-temperature scanning electron microscopy of particle-exposed mouse lung.

Inflated frozen mouse lungs were examined using low-temperature scanning electron microscopy (LTSEM) following bulk fracture under vacuum. Various aspects of pulmonary architecture were identified and correlated with structures revealed by SEM following conventional fixation and preparation techniques. Surface etching of selected samples was performed by radiant heating, revealing characteristic cytoplasmic, nuclear and extracellular lattice patterns resulting from ice crystal formation during freezing. These patterns aided in distinguishing between intra- and extracellular spaces. Pulmonary fluids such as mucus and surfactant were identified. Iron oxide particles were introduced into the lungs of some animals by intratracheal instillation and were subsequently identified in frozen-hydrated lung tissue using characteristic X-ray identification and mapping techniques. Particles were observed both intra-and extracellularly and were commonly found in large deposits. These observations confirm the utility of LTSEM techniques for examination of particles within pulmonary tissue. Particle exposure by intratracheal instillation was found to result in a non-uniform distributional pattern.

Air Pollution↗

PubMed1983

Thermal modification of chrysotile asbestos: evidence for decreased cytotoxicity.

Many asbestiform minerals exhibit temperature-dependent thermoluminescence. Since thermoluminescence involves electronic transitions within crystalline materials, the effect of temperature on asbestos cytotoxicity was evaluated. Heat pretreatment of Canadian chrysotile asbestos reduces its cytotoxicity towards cultured human fibroblasts and bovine alveolar macrophages. When monitored 44 hr after the addition of either 200 degrees C or 400 degrees C heat-pretreated asbestos, alveolar macrophage viability was approximately 40% higher than comparable amounts of unheated asbestos. Similarly, asbestos toxicity, expressed as fibroblast growth inhibition, was inversely related to the asbestos pretreatment temperature in the following manner, 70 degrees C greater than 200 degrees C greater than 400 degrees C = unexposed fibroblast controls. Pretreatment of chrysotile asbestos to 400 degrees C reduced its adsorptive capacity for bovine serum albumin by 25%. Furthermore, asbestos heated to 200 degrees C followed by irradiation with 4 MeV X-rays (4500 rads) resulted in reactivation of asbestos cytotoxicity. Scanning electron microscopy indicated that the ratios of free to fiber-associated alveolar macrophages and the fiber fragment size distributions were unaffected by either heat pretreatment or X-ray irradiation. These observations strongly suggest that the surface charge characteristics and electronic state of asbestos fibers may be responsible for its biological activity.

Adsorption↗

PubMed1982

Surface morphology and functional studies of human alveolar macrophages from cigarette smokers and nonsmokers.

The surface of macrophages inhabiting the peritoneal and alveolar spaces is pleomorphic in structure. The internal structure of these cells has been widely described and is not discussed here. Although external cell morphology has been well characterized by many researchers, this subject has not been reviewed. This review, therefore, describes in detail the surface features of macrophages as well as factors affecting macrophage morphology. Morphological studies of human cells are emphasized. Functional studies are presented and, when possible, morphological parameters are correlated with cell function. Because cigarette smoking has been well studied, the effects of this pulmonary insult are described in detail.

Anesthetics, Local↗

PubMed1982

Functional evaluation of lung macrophages from cigarette smokers and nonsmokers.

The in vitro function of pulmonary alveolar macrophages (PAM) was compared for human smokers and nonsmokers. Initial studies demonstrated the feasibility of shipping lavaged cells on ice with storage up to 6 hr. Comparative studies were performed to evaluate ideal culture conditions including media composition, preincubation period, and phagocytic variables. Smokers had a six-fold enhancement in lavagable macrophages compared to nonsmokers. Macrophages from smokers demonstrated a decreased phagocytic capability compared to nonsmokers. The effects of cigarette smoking on phagocytosis were observed over a wide range of challenge periods using either fetal or newborn bovine serum (FBS or NBS). Regardless of smoking history, enhanced phagocytosis was observed with media containing NBS compared to FBS. No effects on in vitro viability, attachment, or adherence were observed.

Adult↗

PubMed1980

Morphological studies of cultured human pulmonary macrophages.

A morphological classification scheme is developed for the quantitative in vitro examination, by scanning electron microscopy (SEM), of pulmonary alveolar macrophages (AM) from human cigarette smokers and nonsmokers. The AM were obtained by bronchopulmonary lavage, allowed to attach to glass coverslips in a serum containing medium, cultured for 1, 2, or 25 hours, and examined in the SEM. Fifty cells per sample were randomly selected for detailed morphological analysis using a predetermined sampling grid. Area, form, degree of cell spreading, and the relative abundances of surface features, including ruffles, filopodia, blebs, microvilli, multiple features, and no surface features were quantified. Smoker AM had a greater incidence of ruffles, filopodia, multiple features, and rounded cells; nonsmoker AM had greater incidences of featureless and spread cells. Microvilli and blebs were observed infrequently and displayed no trends with respect to differences between smokers and nonsmokers. The incidence of filopodia, multiple features, and intermediate shapes generally increased with increasing culture time, and a decreasing incidence with increasing time in culture was observed for featureless and spread cells. For the 1- and 2-hour culture periods, slightly greater sizes, size variances, form factors, and form factor variances were observed for smoker AM; however, after 25 hours in culture, nonsmoker AM populations possessed these characteristics. Area frequency distributions appeared to be logarithmically normal in distribution. Statistical analyses indicated that for area and form, the greatest variance was due to variations among the individuals lavaged.

Cell Adhesion↗

PubMedDate not supplied

Chronic granulomatous pneumonia and lymphocytic responses induced by inhaled beryllium metal in A/J and C3H/HeJ mice.

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). Key to the pathogenesis of CBD is a delayed-type hypersensitivity reaction, in which Be most likely functions as a hapten and acts as a Class II-restricted antigen, stimulating local proliferation and accumulation in the lung of Be-specific CD4+ T cells. The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2a haplotype) and C3H/HeJ (H-2a) mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro. Responses were similar in both strains of mice. The lungs of all Be-exposed mice had interstitial compact aggregates of lymphocytes, and granulomatous pneumonia characterized by vacuolated macrophages and giant cells in alveoli, neutrophils in alveoli and alveolar septa, multifocal interstitial granulomas, and interstitial infiltrates of lymphocytes, plasma cells, monocytes, and macrophages. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO4 in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans' giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease.

Administration, Inhalation↗

PubMedDate not supplied

Carcinogenic responses of transgenic heterozygous p53 knockout mice to inhaled 239PuO2 or metallic beryllium.

The transgenic heterozygous p53+/- knockout mouse has been a model for assessing the tumorigenicity of selected carcinogens administered by noninhalation routes of exposure. The sensitivity of the model for predicting cancer by inhaled chemicals has not been examined. This study addresses this issue by acutely exposing p53+/- mice of both sexes by nose-only inhalation to either air (controls), or to 1 of 2 levels of 239PuO2 (500 or 100 Bq 239Pu) or beryllium (Be) metal (60 or 15 micrograms). Additional wild-type p53+/+ mice were exposed by inhalation to either 500 Bq of 239PuO2 or 60 micrograms of Be metal. These carcinogens were selected because they operate by differing mechanisms and because of their use in other pulmonary carcinogenesis studies in our laboratory. Four or 5 of the 15 mice per sex from each group were sacrificed 6 mo after exposure, and only 2 pulmonary neoplasms were observed. The remainder of the mice were held for life-span observation and euthanasia as they became moribund. Survival of the p53+/- knockout mice was reduced compared to the p53+/+ wild-type mice. No lung neoplasms were observed in p53+/- mice exposed to air alone. Eleven of the p53+/- mice inhaling 239PuO2 developed pulmonary neoplasms. Seven p53+/+ mice exposed to 239PuO2 also developed pulmonary neoplasms, but the latency period for pulmonary neoplasia was significantly shorter in the p53+/ mice. Four pulmonary neoplasms were observed in p53+/- mice exposed to the higher dose of Be, whereas none were observed in the wild-type mice or in the heterozygous mice exposed to the lower dose of Be. Thus, both p53+/- and p53+/+ mice were susceptible to 239Pu-induced carcinogenesis, whereas the p53+/- but not the p53+/+ mice were susceptible to Be-induced carcinogenesis. However, only 2 pulmonary neoplasms (1 in each of the 239PuO2 exposure groups) were observed in the 59 p53+/ mice that were sacrificed or euthanatized within 9 mo after exposure, indicating that the p53+/- knockout mouse might not be appropriate for a 6-mo model of carcinogenesis for these inhaled carcinogens.

Adenocarcinoma↗