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Biomedical subjects

R O McClellan

Publications and source records attributed to R O McClellan.

At least 55 records · Page 3Linked to original sources
PubMed1987

Effects of protraction of the alpha dose to the lungs of mice by repeated inhalation exposure to aerosols of 239PuO2.

To determine the long-term biological effects of protracted alpha irradiation of the lung, 84-day-old C57BL/6J mice were repeatedly exposed by inhalation to aerosols of 239PuO2 every other month for up to six exposures in 10 months to reestablish lung burdens of 20, 90, or 460 Bq. Other mice were exposed only once when either 84 or 460 days of age to achieve desired initial lung burdens of 20, 90, 460, or 2300 Bq. Suitable control groups were maintained. Groups of mice with similar cumulative alpha doses to the lung had 3.4 to 4.4 times greater incidence of pulmonary tumors (adenomas and adenocarcinomas) when the dose to the lung was protracted by the repeated inhalation exposures compared to mice that received a single inhalation exposure. Excess pulmonary tumors per unit dose to the lung were also greater in groups of repeatedly exposed mice compared to those exposed only once. Repeatedly exposed mice also died earlier with pulmonary tumors than did those exposed once. It appears that protraction of an alpha dose to lungs increases the carcinogenic risk of inhaled 239PuO2 in mice.

Administration, Inhalation↗
PubMed1986

Binding of nitropyrenes and benzo[a]pyrene to mouse lung deoxyribonucleic acid after pretreatment with inducing agents.

In assessing the biological effects of exposure to a complex chemical mixture, it is important to determine how the behavior of one compound may be influenced by the presence of other compounds in the mixture. In this study the effect of pre-exposure to an organic extract of diesel exhaust or to selected compounds in diesel exhaust on the binding of diesel exhaust compounds to DNA was determined. The amount of radiolabel covalently bound to mouse lung DNA following intratracheal administration of radiolabeled benzo[a]pyrene (BaP), 1-nitropyrene, 1,3,6-trinitropyrene, or a mixture of dinitropyrene was determined following pretreatment with benzo[a]pyrene, 1-nitropyrene, and diesel exhaust extract. Male CD-1 mice, 15-18 weeks of age, received 10 mg/kg of putative inducing agents by intratracheal instillation and, after 24 hr, 0.03 to 1.2 mg/kg radiolabeled putative DNA binding agents. Lung DNA was extracted, and covalent binding was quantitated by liquid scintillation spectroscopy. 1-Nitropyrene was a potent lung DNA binding agent in the absence of inducing agents [Covalent Binding Index (CBI) = 970] and was extremely potent after benzo[a]pyrene pretreatment (CBI = 21,540, comparable to the CBI for aflatoxin B1). Similar results were obtained for DNA binding of dinitropyrene and trinitropyrene with and without BaP pretreatment. DNA binding of BaP was lower (CBI = 40) and less inducible (BaP-pretreatment CBI = 230). Pretreatment with diesel extract caused an elevation in the binding of benzo[a]pyrene but little or no elevation in the binding of the nitropyrenes. Pretreatment with 1-nitropyrene did not increase significantly DNA binding of any of the agents tested. These results indicate that nitropyrenes bind readily to lung DNA and this binding may be increased in the presence of respirable mixtures, especially those containing inducing agents such as BaP.

Aflatoxin B1↗
PubMed1986

Comparative acute toxicity of four nickel compounds to F344 rat lung.

Nickel subsulfide (Ni3S2), nickel chloride (NiCl2), nickel sulfate (NiSO4), and nickel oxide (NiO) are compounds of widely differing solubility encountered in the nickel-refining and electroplating industries. Inhalation is a common route of exposure and toxicity to the respiratory tract is possible. The purpose of this study was to evaluate the biochemical, cytological, and morphological changes in lung following administration of these compounds by intratracheal instillation. F344/Crl rats were administered a single dose of nickel compound containing 0.0, 0.01, 0.10, or 1.0 mumol Ni by intratracheal instillation. Rats were sacrificed at 1 or 7 days after compound administration, with half the animals in each exposure group taken for determination of nickel lung burden and the remaining half used for evaluation of biochemical, cytological, and histological changes. In the latter group, the right lung was lavaged and the fluid obtained was analyzed for indicators of pulmonary inflammation: lactate dehydrogenase (LDH), beta-glucuronidase (BG), total protein (TP), glutathione reductase (GR), glutathione peroxidase (GP), and sialic acid (SA). Total and differential cell counts on cells recovered in lavage fluid were also determined. The left lobe was examined for morphological changes. Clearance of nickel from the lung was most rapid for NiCl2 and NiSO4, followed by Ni3S2 and NiO. Minimal changes in all parameters were observed at 1 day after exposure. No significant changes in any parameter occurred in rats exposed to NiO, while Ni3S2, NiSO4, and NiCl2 caused increased in LDH, BG, TP, GR, SA, and total nucleated cells at 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Mutagenicity of used crankcase oils from diesel and spark ignition automobiles.

The Salmonella mutagenicity assay was used to compare the mutagenic activity of used crankcase oil (UCO) from diesel and spark-ignition (gasoline) engine passenger cars. UCO samples were obtained during periodic oil changes from 9 spark-ignition and 10 diesel-powered vehicles. Five samples of unused motor oil were also tested. Direct tests of UCO did not detect mutagenic activity in Salmonella typhimurium strain TA-98. Therefore, an extraction procedure was used to concentrate the mutagens and remove interfering chemicals. Extracts were tested both with and without Aroclor-1254-induced rat liver homogenate fraction (S-9). Dose-dependent mutagenicity with and without S-9 was observed in both diesel and spark-ignition engine UCO extracts. Mutagenic activity was also found in unused oil extracts, but it was lower than that in UCO extracts and generally required addition of S-9. The mutagenic potency of diesel UCO extracts was similar to that of gasoline UCO extracts, both with and without addition of S-9. This indicated that potential health risks associated with disposal, handling, and recycling of diesel UCO may not be significantly different from those of UCO from gasoline engines.

Animals↗
PubMed1986

Comparative cytotoxicity of four nickel compounds to canine and rodent alveolar macrophages in vitro.

Nickel subsulfide (Ni3S2), nickel sulfate (NiSO4), nickel chloride (NiCl2), and nickel oxide (NiO), are four compounds encountered by workers in the nickel-refining and electroplating industries. These compounds were tested for their relative toxicity to beagle dog and F344/Crl rat alveolar macrophages in vitro. Dog alveolar macrophages were at least 10 times more sensitive to the effects of each of the 4 nickel compounds than were rat alveolar macrophages. Toxicity ranking of the four nickel compounds to macrophages from both species was Ni3S2 greater than NiCl2 approximately NiSO4 greater than NiO.

Animals↗
PubMed1986

Toxicological effects of emissions from diesel engines.

The 29 papers at this international symposium demonstrate the success of the past decade's research on diesel exhaust emissions. The observations made in different countries which have utilized biological systems ranging from macromolecules to cells and tissues to populations of animals and people are highly complementary. The findings presented here, combined with estimates of diesel exhaust exposure, provide the basis for development of qualitative and, perhaps semi-quantitative, estimates of cancer risk from exposure to diesel exhaust. In addition, the research reported provides valuable insight into the mechanisms by which inhalation of complex mixtures may cause lung cancer.

Animals↗
PubMed1986

Disposition and metabolism of [14C]dibenzo[c,g]carbazole aerosols in rats after inhalation.

Dibenzo[c,g]carbazole (DBC) is a nitrogen-containing polycyclic aromatic hydrocarbon that has been detected in tobacco tars, industrial oils, and diesel engine exhaust fumes. DBC is carcinogenic in respiratory tract tissue of hamsters and in lungs, kidneys, and livers of mice. The purpose of this research was to determine the respiratory tract deposition, distribution in tissues, metabolism, and excretion of DBC in rats after inhalation. Rats were exposed nose-only to 1.1 or 13 micrograms [14C]DBC/liter air for 60 min. Activity median aerodynamic diameters for the two concentrations of DBC ranged from 0.7 to 0.8 micron. Urine, feces, and selected tissues were collected for various times after exposure. The fractional deposition for the 1.1 and 13 micrograms/liter exposure concentrations was similar, 13 and 16%, respectively. The dominant route of excretion of 14C following exposure to either concentration of DBC was the feces, accounting for approximately 95% of the total 14C eliminated. Half-time for fecal excretion was 20 +/- 6 hr (means +/- SE). Gastrointestinal absorption of [14C]DBC was 43%. Radioactivity was widely distributed to all tissues examined, with the respiratory tract (lung, trachea, larynx, and nasal turbinates), upper gastrointestinal tract (stomach and small intestine), the liver, and the adrenals containing the highest concentrations of [14C]DBC equivalents within 1 hr after exposure. At both concentrations of DBC tested, clearance of 14C from tissues was rapid, with approximately 60 to 98% of the initial tissue burden being cleared with half-times ranging from 1 to 16 hr. The remaining 2 to 40% in the tissues was cleared with half-times that ranged from 1.5 to 14 days. Several metabolites were detected in the urine and feces, none of which appeared to be either glucuronide or sulfate conjugates. Small quantities of [14C]DBC were detected in the urine, although quantities were less than 1% of the initial respiratory tract burden of [14C]DBC. The results from this research indicate that DBC was rapidly absorbed from the lungs and translocated to many tissues. Prior to elimination, primarily in the feces, DBC was extensively metabolized. There appeared to be no effect of exposure concentration on the toxicokinetics of inhaled DBC.

Aerosols↗
PubMed1985

Health effects of diesel exhaust. A contemporary air pollution issue.

Extracts of diesel exhaust particles are mutagenic in bacterial and mammalian cell assays; they contain hundreds of identifiable organic compounds, some of which are known mutagens and carcinogens. The particles are readily respired and about 20% to 30% of them are deposited in the pulmonary region, where they are retained for long periods. At low diesel exhaust concentrations, typical of those likely for human exposure, particle deposition and clearance rates are essentially normal and particle concentrations in the pulmonary region are expected to remain quite low. At very high concentrations of diesel exhaust, clearance processes may be overwhelmed and lung burdens of particles may continue to increase over long periods. Evidence from laboratory animals suggests that pulmonary injury and reduced respiratory function would occur in humans at these high concentrations. Epidemiologic data and laboratory studies appear to indicate that the human lung cancer risk from exposure to diesel exhaust would be quite low, even if use of diesel vehicles increased substantially.

Animals↗
PubMed1985

Biliary excretion and enterohepatic circulation of 1-nitropyrene metabolites in Fischer-344 rats.

1-Nitropyrene (1-NP), present in diesel engine emissions, is a potent mutagen to bacteria, such as those found in mammalian intestinal tract, which contain nitroreductase enzymes. The purposes of this study were to determine the importance of bile as a route of excretion of 1-NP metabolites and to determine if reabsorption of biliary metabolites required the presence of intestinal bacteria. The bile ducts of male Fischer-344 rats were cannulated, 0.3 or 1.2 mumoles [3H]1-NP was given i.v., and bile, urine, and feces were collected for 24 hr. Biliary excretion accounted for 70 (80%) or 170 (60%) nmoles of [3H]1-NP after the low and high dose, respectively, with half-times for excretion of 1.7 hr +/- 0.3 (+/- S.E.M.) and 3.4 hr +/- 1.6 (+/- S.E.M.). Excretion of [3H]1-NP equivalents in the urine was linearly related to dose, with 6 or 16 nmoles (8%) excreted in 24 hr. At the low dose, more radioactivity appeared in the urine in control rats compared to bile-duct cannulated rats, suggesting that reabsorption of 1-NP metabolites occurred. Pretreatment of rats with orally administered antibiotics prior to i.v. injection of 0.3 mumole [3H]1-NP decreased radioactivity excreted in urine compared to untreated controls, suggesting that intestinal microorganisms may alter the biliary metabolites of 1-NP to facilitate reabsorption. Pretreatment of rats with buthionine sulfoximine, a glutathione depletor, decreased the excretion of certain biliary metabolites, suggesting that they were mercapturic acids of 1-NP metabolites. In summary, the results of these studies indicate that bile was an important route of excretion of nitropyrene metabolites. A portion of the excreted metabolites was reabsorbed from the gut, and this reabsorption required the presence of gut microorganisms.

Animals↗
PubMed1985

Projected uptake and toxicity of selenium compounds from the environment.

Industrial workers and members of the general public may be exposed to selenium by inhalation of selenium in the workplace or atmosphere or by ingestion of selenium in food. A model has been developed to evaluate the potential uptake of selenium in body tissues by these two exposure routes. Rates were estimated for transport of selenium between five compartments including lung, gastrointestinal tract, blood, liver and other tissues. Results of model simulations were compared to published tissue distribution information obtained from single inhalation exposures of rats and dogs to radiolabeled selenium compounds at concentrations from 20 mg/m3 to 20 micrograms/m3 with initial body burdens of selenium ranging from 28 to 0.09 micrograms Se/kg body wt. The model was then modified to predict equilibrium organ concentrations of selenium in people after continual exposure to selenium in the air or in the diet. Daily intake levels of 100 micrograms/day and a fractional absorption value of 0.8 were used. With an air concentration of 1 ng Se/m3, model predictions indicated that most of the total body selenium in people is likely to come from their diet because selenium in the urban atmosphere contributes a very small part of the total body selenium. However, continual inhalation of selenium at the threshold limit value (TLV; 200 micrograms/m3) could contribute significantly to the total body burden of selenium. Levels of selenium predicted in lung, liver, and blood after inhalation of selenium at the TLV were 22,000, 1200, and 440 ng Se/g tissue. Predicted lung concentrations were near those that produced toxic effects in animals after ingestion of Se.

Absorption↗
PubMed1985

Metabolism of 1-[14C]nitropyrene in respiratory tract tissue of rats exposed to diesel exhaust.

The purpose of this study was to determine how prior exposure of rats to graded concentrations of diesel exhaust would affect respiratory tract tissue metabolism of 1-nitropyrene (NP), a known constituent of diesel exhaust. Rats were exposed (whole body) 7 hr/day, 5 days/week for 4 weeks to clean air (controls) or to diluted diesel exhaust containing concentrations of 350, 3300, and 7400 micrograms particles/m3. After exposures, nasal tissue and lungs from rats were tested for their ability to metabolize NP. Rat nasal tissue was incubated for 10 min with 20 microM 1-[14C]NP. Isolated perfused rat lungs were perfused for 90 min with 25 microM 1-[14C]NP. NP metabolites formed in rat nasal tissue and the isolated perfused rat lung were separated by high-pressure liquid chromatography. Exposure of rats to 7400 micrograms particles/m3 for 4 weeks resulted in significant increases (twofold) in rates of NP metabolism in both nasal tissue (440 pmol/mg protein/min) and the isolated perfused rat lung (112 nmol/g lung). Exposure of rats to lower concentrations of diesel exhaust did not increase the rates of NP metabolism in either rat nasal tissue or perfused rat lungs. In all cases, the major metabolites of NP formed in nasal tissue and perfused lungs were 3-, 6-, and 8-hydroxy-1-nitropyrene and 4,5-dihydro-4,5-dihydroxy-1-nitropyrene. A fourfold increase was observed in the amounts of 14C covalently bound in lungs from rats exposed to 7400 micrograms particles/m3. The results from this study indicate that exposure to diesel exhaust particles significantly alters metabolism and subsequent covalent binding of NP.

Animals↗
PubMed1985

New approaches for the evaluation of pulmonary toxicity: bronchoalveolar lavage fluid analysis.

Analysis of bronchoalveolar lavage fluid (BAL) is an effective method of detecting an inflammatory response in the lungs of animals in toxicological studies. Alterations in BAL that are the most sensitive indications of an inflammatory response are an increased content of serum proteins and an influx of neutrophils (PMNs). Elevation of the cytoplasmic enzyme lactate dehydrogenase (LDH) is a useful indicator of cytotoxicity. The pulmonary inflammatory response to particles (either mineral dusts or soot) in the lung includes greatly increased activities of such lysosomal enzymes as beta-glucuronidase and beta-N-acetylglucosaminidase in BAL. Examination of alterations in BAL in rats and mice during chronic exposure to high levels of diluted diesel exhaust revealed that steadily increasing levels of LDH, beta-glucuronidase, and hydroxyproline in BAL correlated better with the development of pulmonary fibrosis than did measures of an inflammatory response (protein, PMNs). Analysis of BAL has proven useful, both for detection of lung injury in toxicological screening tests and for determination of the mechanisms of developing chronic lung disease. Future work shows promise of developing assays for BAL analysis to identify the specific site or type of pulmonary injury present.

Animals↗
PubMed1985

Effects of inhaled diesel exhaust on immune responses after lung immunization.

The inhalation of diesel exhaust particles and the accumulation of these particles in the lung-associated lymph nodes could alter the development of immune responses after lung immunization. To study this possibility, Fischer 344 rats and CD-1 mice were exposed to three levels of diesel exhaust (nominal concentration--7000, 3500, or 350 micrograms particles/m3). Chamber controls and exposed animals were immunized by intratracheal instillation of sheep red blood cells (SRBC) after 6, 12, 18, and 24 months of exposure. The number of anti-SRBC IgM antibody-forming cells (AFC) in the lung-associated lymph nodes and spleen was evaluated after immunization. The lung-associated lymph nodes from rats and mice exposed to the high levels of diesel exhaust were black with accumulated diesel particles, and the number of lymphoid cells was significantly elevated at each sacrifice time, while rats exposed to the medium level of diesel exhaust also had elevated numbers of cells in these tissues at 12, 18, and 24 months of exposure. The total number of AFC in the lung-associated lymph nodes was significantly elevated (p less than 0.05) in rats exposed to medium and high levels of diesel exhaust, but no significant effects were observed in exposed mice. Data expressed as AFC/10(6) lymphoid cells in rats and mice, and the level of specific IgM, IgG, or IgA antibody in rat sera were not significantly altered. We conclude that the increased cellularity, and the presence of diesel particles in the lung-associated lymph nodes, had a minimal effect on the immune and antigen filtration functions of these tissues.

Animals↗
PubMed1985

Comparison of lung burdens of inhaled particles of rats exposed during the day or night.

Inhalation studies frequently involve daytime exposures of nocturnal animals to toxicants. Such exposures may result in different respiratory tract depositions than would be obtained if rodents were exposed at night. Our study assessed the effect of night versus day exposures on lung burdens of particles inhaled by Fischer 344 rats. One group of 15 female rats was exposed to 0.3 micron volume median diameter particles of gallium oxide (Ga2O3) for 11.2 h during the day and a second group of 15 female rats was exposed to the same aerosol for 11.2 h at night. Gallium in the lungs at the end of exposure was measured by electrothermal atomic absorption spectrometry. Rats exposed during the night had significantly (p less than 0.05) higher lung burdens than day-exposed rats when burdens were expressed as either microgram Ga2O3/lung (mean +/- SD = 896 +/- 175 versus 698 +/- 150) or microgram Ga2O3/g lung (mean +/- SD = 683 +/- 134 versus 465 +/- 103). The greater amount of material in lungs of rats exposed at night probably reflected increased ventilation accompanying nocturnal activity.

Aerosols↗