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Biomedical subjects

E B Barr

Publications and source records attributed to E B Barr.

At least 37 records · Page 2Linked to original sources
PubMed1995

A comparison of the inflammatory response of the lung to inhaled versus instilled particles in F344 rats.

The potential pulmonary toxicity of poorly soluble airborne dusts generated in industrial and environmental settings is often evaluated by inhalation studies in rodents. Studies using intratracheal instillation of particles have been suggested as a less expensive alternative. We conducted a study to compare the inflammatory response of the lung to instilled versus inhaled particles. In one study, female F344/N rats, 11-13 weeks of age, were exposed for 6 hr/day, 5 days/week for 4 weeks by inhalation to 0, 0.1, 1.0, or 10 mg/m3 of either alpha-quartz (toxic particle) or TiO2 (relatively low toxicity particle) and the lung burdens were determined at 1 week after the end of the exposure. The lungs were evaluated by analysis of bronchoalveolar lavage fluid (BALF) at 1, 8, and 24 weeks after the end of the exposure and by histopathology at 24 weeks. In a second study, rats were exposed by instillation to the lung burdens present in the preceding study at 1 week after the inhalation exposure, and the rats were evaluated in the same manner as in the inhalation study. In general, the degree of alveolitis, as evaluated by histopathology and BALF analysis, was similar by the two methods of exposure. With lung burdens up to 750 micrograms/g lung, the TiO2 elicited no changes in BALF parameters at any time by either method of exposure, nor was any histopathology observed. The BALF changes elicited by alpha-quartz were of approximately the same magnitude and followed the same time course by either exposure method with the lowest dose delivered to the lung by either method being a "no-effect" dose. At the highest dose, microgranulomas were observed in bronchial-associated lymphoid tissue (BALT) in both sets of rats. However, the highest inhalation exposure induced pleural granulomatous lesions that were not observed in the animals instilled with alpha-quartz. The results indicate that the relative potentials of the two materials to produce bronchoalveolitis and granulomatous lesions in BALT could be appropriately evaluated using either intratracheal or inhalation exposures.

Administration, Inhalation↗
PubMed1995

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

Diesel exhaust (DE) is a known pulmonary carcinogen in rats, and the carcinogenic response is known to require the presence of soot. Many estimates of human lung cancer risk from inhaled DE have been developed from rat bioassay data or from the comparative mutagenic potencies of DE soot extract and known human chemical carcinogens. To explore the importance of the DE soot-associated organic compounds in the lung tumor response of rats, male and female F344 rats were exposed chronically to diluted whole DE or aerosolized carbon black (CB) 16 hr/day, 5 days/week at target particle concentrations of 2.5 mg/m3 (LDE, LCB) or 6.5 mg/m3 (HDE, HCB) or to filtered air. The CB served as a surrogate for the elemental carbon matrix of DE soot. Considering both the mass fraction of solvent-extractable matter and its mutagenicity in the Ames Salmonella assay, the mutagenicity in revertants per unit particle mass of the CB was three orders of magnitude less than that of the DE soot. Both DE soot and CB particles accumulated progressively in the lungs of exposed rats, but the rate of accumulation was higher for DE soot. In general, DE and CB caused similar, dose-related, nonneoplastic lesions. CB and DE caused significant, exposure concentration-related increases, of similar magnitudes, in the incidences and prevalences of the same types of malignant and benign lung neoplasms in female rats. The incidences of neoplasms were much lower in males than females, and the incidences were slightly higher among DE- than CB-exposed males. Survival was shortened in the CB-exposed males, and the shortened survival may have suppressed the expression of carcinogenicity as measured by crude incidence. Logistic regression modeling did not demonstrate significant differences between the carcinogenic potencies of CB and DE in either gender. The results suggest that the organic fraction of DE may not play an important role in the carcinogenicity of DE in rats.

Administration, Inhalation↗
PubMed1995

Particle clearance and histopathology in lungs of F344/N rats and B6C3F1 mice inhaling nickel oxide or nickel sulfate.

The goals of this study were to (1) determine the effects of repeated inhalation of relatively insoluble nickel oxide (NiO) and highly soluble nickel sulfate hexahydrate (NiSO4.6H2O) on lung particle clearance, (2) investigate the effects of repeated inhalation of NiO or NiSO4 on the pulmonary clearance of subsequently inhaled 85Sr-labeled microspheres, (3) correlate the observed effects on clearance with accumulated Ni lung burden and associated pathological changes in the lung, and (4) compare responses in F344 rats and B6C3F1 mice. Male F344/N rats and B6C3F1 mice were exposed whole-body to either NiO or NiSO4.6H2O 6 hr/day, 5 days/week for up to 6 months. NiO exposure concentrations were 0, 0.62, and 2.5 mg NiO/m3 for rats and 0, 1.25, and 5.0 mg NiO/m3 for mice. NiSO4.6H2O exposure concentrations were 0, 0.12, and 0.5 mg NiSO4.6H2O/m3 for rats and 0, 0.25, and 1.0 mg NiSO4.6H2O/m3 for mice. After 2 and 6 months of whole-body exposure, groups of rats and mice were acutely exposed nose-only to 63NiO (NiO-exposed animals only), 63NiSO4.6H2O (NiSO4.6H2O-exposed animals only), or to 85Sr-labeled polystyrene latex (PSL) microspheres (both NiO- and NiSO4.6H2O-exposed animals) to evaluate lung clearance. In addition, groups of rats and mice were euthanized after 2 and 6 months of exposure and at 2 and 4 months after the whole-body exposures were completed to evaluate histopathological changes in the left lung and to quantitate Ni in the right lung. Repeated inhalation of NiO results in accumulation of Ni in lungs of both rats and mice, but to a greater extent in lungs of rats. During the 4 months after the end of the whole-body exposures, some clearance of the accumulated Ni burden occurred from the lungs of rats and mice exposed to the lower, but not the higher NiO exposure concentrations. Clearance of acutely inhaled 63NiO was also impaired in both rats and mice, with the extent of impairment related to both exposure concentration and duration. However, the clearance of acutely inhaled 85Sr PSL microspheres was not impaired. The repeated inhalation of NiO resulted in alveolar macrophage (AM) hyperplasia with accumulation of NiO particles in both rats and mice, chronic alveolitis in rats, and interstitial pneumonia in mice. These lesions persisted throughout the 4-month recovery period after the NiO whole-body exposures were terminated. In contrast, repeated inhalation of NiSO4.6H2O did not result in accumulation of Ni in lungs of either rats or mice and did not affect the clearance of 63NiSO4.6H2O inhaled after either 2 or 6 months of NiSO4.6H2O exposure. Clearance of the 85Sr-labeled microspheres was significantly impaired only in rats exposed to the microspheres after 2 months of exposure to NiSO4.6H2O. Histopathological changes in rats were qualitatively similar to those seen in NiO-exposed rats. Only minimal histopathological changes were observed in NiSO4.6H2O-exposed mice. These results suggest that repeated inhalation of NiO at levels resulting in AM hyperplasia and alveolitis may impair clearance of subsequently inhaled NiO. The potential effects of repeated inhalation of soluble NiSO4.6H2O on the clearance of subsequently inhaled poorly soluble particles are less clear.

Administration, Inhalation↗
PubMed1994

Pulmonary toxicity of inhaled diesel exhaust and carbon black in chronically exposed rats. Part I: Neoplastic and nonneoplastic lung lesions.

This study compared the pulmonary carcinogenicities and selected noncancer effects produced by chronic exposure of rats at high rates to diesel exhaust and carbon black. The comparison was intended to provide insight into the likely importance of the mutagenic organic compounds associated with the soot portion of diesel exhaust in inducing pulmonary carcinogenicity in diesel exhaust-exposed rats. The role of the organic fraction has become important in judging the usefulness of the substantial data base on carcinogenicity in rats for predicting lung cancer risk for humans, and for determining the most appropriate method of extrapolating results across species and exposure concentrations. Rats were exposed chronically to either diesel exhaust or carbon black, which served as a surrogate for diesel exhaust soot with much reduced mutagenic activity associated with its organic fraction. The sequestration of particles in the lung and the induction of pulmonary neoplasia and non-neoplastic changes in the lung were compared in detail. Samples also were provided to collaborators to examine adduct formation in lung DNA and hemoglobin. Approximately 140 female and 140 male F344/N rats were exposed for 16 hours per day, 5 days per week for up to 24 months, beginning at eight weeks of age, to diesel exhaust or carbon black at 2.5 mg or at 6.5 mg particles/m3 of air, or to clean air as controls. The diesel exhaust was generated by light-duty engines burning certification fuel and operating on an urban-duty cycle. The carbon black was selected because it had particle size and surface area characteristics similar to those of diesel exhaust soot, but markedly less mutagenic activity associated with its organic fraction when analyzed using procedures typically used in studies of diesel soot. Rats were killed after 3, 6, 12, 18, or 23 months of exposure to measure lung and lung-associated lymph node burdens of particles, lung weight, bronchoalveolar lavage indicators of inflammation, DNA adducts in whole lung and alveolar type II cells, and chromosome injury in circulating lymphocytes, and to perform histopathologic assessment. In addition, after 3 and 18 months of chronic exposure, one group of rats was acutely exposed to radiolabeled carbon black particles or to fluorescent microspheres. These exposures were conducted to examine the clearance of radiolabeled particles and the sequestration of the fluorescent microspheres in the lungs. These experiments provided information on clearance overload and particle dosimetry. The growth characteristics of lung neoplasms also were examined by transplanting neoplastic cells into athymic mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Air Pollutants, Occupational↗
PubMed1993

Thirteen-week, repeated inhalation exposure of F344/N rats and B6C3F1 mice to ferrocene.

Ferrocene (dicyclopentadienyl iron; CAS No. 102-54-5) is a relatively volatile compound used as a chemical intermediate, a catalyst, and an antiknock additive in gasoline. This organometallic chemical is of particular interest because of its structural similarities to other metallocenes, some of which are carcinogenic. F344/N rats and B6C3F1 mice were exposed to 0, 3.0, 10, and 30 mg ferrocene vapor/m3, 6 hr/day, 5 days/week, for 13 weeks. During these exposures, no rats or mice died, nor were any clinical signs of ferrocene-related toxicity observed. At the end of the exposures, male rats exposed to the lowest and highest level of ferrocene had decreased body weight gains compared to filtered-air-exposed control male rats, while body weight gains for all groups of both ferrocene- and filtered-air-exposed female rats were similar. Male mice exposed to ferrocene had no differences in body weight gains, compared to controls, but female mice had decreases in body weight gains at the 10 and 30 mg/m3 exposure levels. There were exposure concentration- and exposure-time-related increases in lung burdens of iron. The mean iron lung burden in rats exposed to 30 mg ferrocene vapor/m3 for 90 days was four times greater than the burden in control rats. No exposure-related changes in respiratory function, lung biochemistry, bronchoalveolar lavage cytology, total lung collagen, clinical chemistry, and hematology parameters were observed. This suggests that the accumulations of iron in lung did not cause an inflammatory response nor any functional impairment of the lung. There were no indications of developing pulmonary fibrosis nor of any hematologic toxicity. No exposure-related gross lesions were seen in any of the rats or mice at necropsy. Exposure-related histopathologic alterations, primarily pigment accumulations, were observed in the nose, larynx, trachea, lung, and liver of both species, and in the kidneys of mice. Lesions were most severe in the nasal olfactory epithelium where pigment accumulation, necrotizing inflammation, metaplasia, and epithelial regeneration occurred. Nasal lesions were observed in all ferrocene-exposed animals and differed only in severity, which was dependent on the exposure concentration. Histochemical stains of these target tissues showed the presence of iron ions. The results suggest that the mechanism of ferrocene toxicity may be the intracellular release of ferrous ion through ferrocene metabolism, followed by either iron-catalyzed lipid peroxidation of cellular membranes or the iron-catalyzed Fenton reaction to form hydroxyl radicals that directly react with other key cellular components, such as protein or DNA.

Administration, Inhalation↗
PubMed1992

The effect of exposure pattern on the accumulation of particles and the response of the lung to inhaled particles.

We hypothesized that a rapid rate of delivery of particles to the lung would overwhelm the normal clearance mechanisms of the lung and result in a higher lung burden of particles and a greater inflammatory response than a slower rate of particle delivery. F344/N rats were exposed over a 12-week period to the same weekly concentration times time product of carbon black (CB) particles, but at three different exposure rates: 3.5 mg/m3, 16 hr/day, 7 days/week; 13 mg/m3, 6 hr/day, 5 days/week; or 98 mg/m3, 4 hr/day, 1 day/week. The intermediate exposure rate was chosen to mimic an occupational work week and to give an 8-hr, time-weighted average exposure equal to the threshold limit value (TLV) for nuisance dusts of the American College of Governmental Industrial Hygienists (10 mg/m3). Pure CB has a lower TLV, 3.5 mg/m3, than nuisance dusts, but this is based on avoidance of excessive dirtiness in the workplace, not on the toxicity of CB. Lung burdens of CB were measured after 3, 6, 9, and 12 weeks of exposure and at 4, 8, 12, 16, and 24 weeks after the exposure ended. The inflammatory response was quantified by analysis of bronchoalveolar lavage fluid (BALF) after 6 and 12 weeks of exposure and at 1, 12, and 24 weeks after exposure. The histopathology of the lung was evaluated at the end of the exposure and at 24 weeks after the exposure. Acquired lung burdens were between 3 and 4 mg/lung at the end of the exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Two-week, repeated inhalation exposure of F344/N rats and B6C3F1 mice to ferrocene.

Ferrocene (dicyclopentadienyl iron; CAS No. 102-54-5) is a relatively volatile, organometallic compound used as a chemical intermediate, a catalyst, and as an antiknock additive in gasoline. It is of particular interest because of its structural similarities to other metallocenes that have been shown to be carcinogenic. F344/N rats and B6C3F1 mice were exposed to 0, 2.5, 5.0, 10, 20, and 40 mg ferrocene vapor/m3, 6 hr/day for 2 weeks. During these exposures, there were no mortality and no observable clinical signs of ferrocene-related toxicity in any of the animals. At the end of the exposures, male rats exposed to the highest level of ferrocene had decreased body-weight gains relative to the weight gained by filtered air-exposed control rats, while body-weight gains for all groups of both ferrocene- and filtered air-exposed female rats were similar. Male mice exposed to the highest level of ferrocene also had decreased body-weight gains, relative to controls, while female mice had relative decreases in body-weight gains at the three highest exposure levels. Male rats had a slight decrease in relative liver weight at the highest level of exposure, whereas no relative differences in organ weights were seen in female rats. Male mice had exposure-relative decreases in liver and spleen weights, and an increase in thymus weights, relative to controls. For female mice, relative decreases in organ weights were seen for brain, liver, and spleen. No exposure-related gross lesions were seen in any of the rats or mice at necropsy. Histopathological examination was done only on the nasal turbinates, lungs, liver, and spleen.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1989

Lung retention and binding of [14C]-1-nitropyrene when inhaled by F344 rats as a pure aerosol or adsorbed to carbon black particles.

1-Nitropyrene (NP), as found in the environment, is more typically associated with carbonaceous particles than found as an aerosol of the pure compound. To determine whether (and why) an association with particles resulted in prolonged lung retention of NP, rats were exposed to 14C-NP as a pure aerosol or adsorbed on carbon black particles. Total 14C retained in the lung was greater at all times from 0.5 h to 30 d after exposure to 14C-NP adsorbed to carbon black particles than after exposure to pure 14C-NP (p less than .05). The fraction of total 14C in lung bound to carbon black particles decreased steadily with time after exposure, indicating in vivo removal of NP from the particles. At 0.5 h after exposure, the fraction of the estimated deposited 14C that was covalently bound to lung macromolecules was twofold greater for NP adsorbed on carbon black than for pure NP. Covalently bound 14C in lungs increased with time after exposure to 14C-NP adsorbed to carbon black, reaching levels of approximately 1% of the deposited radioactivity at 7-30 d after exposure, whereas levels of covalently bound 14C declined with time after exposure to pure NP. Thus, at 30 d after exposure, the amount of 14C covalently bound to lung macromolecules was approximately 10-fold greater (p less than .05) in rats that inhaled 14C-NP adsorbed on carbon black particles than in rats that inhaled pure 14C-NP aerosols. These results suggest that association of NP with carbon black particles augments the interaction of reactive metabolites of NP with target macromolecules. This phenomenon is thought to be related to the slow release of NP from carbon black particles, and may augment the biological effects of inhaled NP when adsorbed on carbon black or similar particles in the environment.

Aerosols↗
PubMed1988

Evaluation of a real-time aerosol monitor (RAM-S) for inhalation studies.

Measurement of the aerosol concentration in inhalation toxicology studies is generally done by gravimetric and/or chemical analysis of filter samples taken over a known period of time at a fixed sampling flow rate. The value obtained represents the time-averaged concentration in an exposure chamber. However, the filter method does not provide information as to the stability of aerosol concentration in "real-time" nor as to the time required for the aerosol concentration to reach the target value during the start-up of exposures. In order to accomplish evaluation of aerosol stability and chamber rise and fall times, a direct measurement device is required. An available real-time aerosol monitor (RAM-S, GCA Corp., Bedford, MA) is a photometer which collects scattered light from an aerosol cloud at a 70 +/- 25 degrees angle. The output signal is 0 to 10 volt with three ranges corresponding to maximum aerosol concentrations of 200, 20, and 2 mg/m3. The performance of the RAM-S was evaluated in inhalation studies involving nickel sulfate hexahydrate, nickel oxide, nickel subsulfide, and azodicarbonamide. Several RAM-S units were calibrated by obtaining both filter samples and voltage readings of a RAM-S simultaneously. Results indicated that the response of the RAM-S instruments was linear. However, the voltage output per given aerosol concentration was different for each compound used. Furthermore, there was interinstrument variability in the voltage response to aerosol concentration of a given compound. At concentrations higher than 100 mg/m3, modification of the flow system in the RAM-S was made to increase the sheath air around the optical system and also to dilute the aerosol concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1988

Factors affecting possible carcinogenicity of inhaled nitropyrene aerosols.

Nitroaromatics in general, and 1-nitropyrene in particular, are potent bacterial mutagens and animal carcinogens. Their importance as possible human carcinogens is difficult to assess because they are usually found in the environment as the products of combustion processes, and so they usually exist with many other compounds associated with airborne particles. The experiments reported here were carried out to determine if the inhalation of particle-associated 1-nitropyrene, or the concomitant exposure to an irritant gas, would alter the tissue distribution of 1-nitropyrene or its metabolites, compared to their distribution after inhalation of pure 1-nitropyrene. These experiments were intended to yield insights into the mechanisms involved in the potential carcinogenicity of particle-associated nitroaromatics as inhaled in the environment from automotive emissions and other sources. Groups of Fischer 344 rats inhaled pure 14C-1-nitropyrene aerosols, with and without coexposure to 5 parts per million sulfur dioxide, or 14C-1-nitropyrene adsorbed onto gallium oxide particles, with and without coexposure to sulfur dioxide, for four weeks. Lung retention of 14C-1-nitropyrene was not prolonged by its association with gallium oxide particles or by coexposure to sulfur dioxide. There was a marked inflammatory and fibrogenic response to the gallium oxide particles. Another set of experiments was carried out in which rats were exposed to 14C-1-nitropyrene either as pure aerosol or adsorbed onto carbon black particles. The amount of 14C in the lung that was bound to carbon black particles steadily decreased with time after exposure, compared to total lung 14C, indicating removal of 14C from the particles. Thirty minutes after exposure, the amount of 14C covalently bound to lung macromolecules, expressed as a percentage of calculated deposited radioactivity, was twofold greater for 1-nitropyrene adsorbed onto carbon black than for 1-nitropyrene alone. The amount of covalently bound 14C increased with time after exposure to 14C-1-nitropyrene adsorbed onto carbon black, reaching a level of approximately 1 percent of deposited radioactivity, 10-fold greater than that seen with pure 14C-1-nitropyrene seven to 30 days after exposure. The level of covalently bound 14C declined steadily after exposure to pure 14C-1-nitropyrene. Carbon black particles associated with adsorbed 1-nitropyrene offer the potential of studying DNA adduct formation in the lung, because DNA modification might be greater after inhalation of 1-nitropyrene adsorbed onto carbon black than after inhalation of pure 1-nitropyrene or 1-nitropyrene associated with metal oxides, such as gallium oxide.(ABSTRACT TRUNCATED AT 400 WORDS)

Air Pollutants↗
PubMed1987

Collection and characterization of aerosols from metal cutting techniques typically used in decommissioning nuclear facilities.

This study was designed to collect and characterize aerosols released during metal cutting activities typically used in decommissioning radioactively contaminated facilities. Such information can guide in the selection of appropriate control technologies for these airborne materials. Mechanical cutting tools evaluated included a multi-wheel pipe cutter, reciprocating saw, band saw, chop saw, and large and small grinding wheels. Melting-vaporization cutting techniques included an oxy-acetylene torch, electric arc cut rod and plasma torch. With the exception of the multi-wheel pipe cutter, all devices created aerosols in the respirable size range (less than 10 micron aerodynamic diameter). Time required to cut 2-in. (5-cm) Schedule 40, Type 304L, stainless steel ranged from about 0.6 min for the plasma torch to about 3.0 min for the reciprocating saw. Aerosol production rate ranged from less than 10 mg/min for the reciprocating saw to more than 3000 mg/min for the electric arc cut rod. Particles from mechanical tools were irregular in shape, whereas particles from vaporization tools were spheres and ultrafine branched-chain aggregates.

Aerosols↗
PubMed1986

Studies of the temporal and spatial distribution of aerosols in multi-tiered inhalation exposure chambers.

Two multi-tiered whole body inhalation exposure chambers with nominal volumes of 1 m3 (H-1000) and 2 m3 (H-2000) were evaluated for their performance in terms of the temporal and spatial distribution of test aerosols within the chamber. Parameters investigated included chamber type, single-chamber-single-aerosol generator versus two-chamber-single-aerosol generator systems, chamber air supply and exhaust systems, particle size, and aerosol diluter type. Results indicated that: 1) particle size has an effect on chamber aerosol concentration distribution, with the larger particle resulting in a higher variation; 2) the single-chamber-single-generator system is more stable than the two-chamber-single-generator system; 3) the H-2000 chamber has a lower aerosol spatial variability than the H-1000 chamber; and 4) the aerosol distribution within the chamber could be improved with the use of a newly designed diluter.

Aerosols↗
PubMedDate not supplied

Pulmonary immunity to ragweed in a Beagle dog model of allergic asthma.

To create an allergy model in the dog, allergic Beagles with high levels of serum immunoglobulin E (IgE) and eosinophilia were bred; resulting puppies were sensitized to ragweed by intraperitoneal (IP) injection within 24 hours of birth through 22 weeks of age. At least 50% of the puppies developed high levels of serum IgE and eosinophilia. As young adults, 6 of these dogs, and 6 control age-matched, nonallergic, nonimmunized dogs were exposed by inhalation to ragweed twice at 13-day intervals, and a third time 45 days later. Total and ragweed-specific serum IgE and ragweed-specific serum IgG were increased significantly in allergic dogs relative to baseline. Allergic dogs had significantly greater levels of antibody specific for ragweed, as well as higher eosinophil counts in the bronchoalveolar lavage fluid, compared to nonallergic dogs. Airway reactivity to histamine in allergic, but not nonallergic dogs, increased significantly after aerosol exposure to ragweed. After a third exposure to ragweed, airway responses to histamine were elevated in the allergic dogs and remained high for at least 5 months. These results demonstrate the potential of the allergic dog model for investigating the underlying pulmonary immune mechanisms and therapeutic treatment of allergic asthma.

Allergens↗
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↗