Lung Burden

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Jurgen Pauluhn - One of the best experts on this subject based on the ideXlab platform.

  • retrospective analysis of 4 week inhalation studies in rats with focus on fate and pulmonary toxicity of two nanosized aluminum oxyhydroxides boehmite and pigment grade iron oxide magnetite the key metric of dose is particle mass and not particle surface area
    Toxicology, 2009
    Co-Authors: Jurgen Pauluhn
    Abstract:

    This paper compares the pulmonary toxicokinetics and toxicodynamics of three different types of poorly soluble dusts examined in repeated rat inhalation bioassays (6 h/day, 5 days/week, 4 weeks). In these studies the fate of particles was studied during a 3–6-month postexposure period. This retrospective analysis included two types of aluminum oxyhydroxides (AlOOH, boehmite), high purity calcined, and agglomerated nanosized aluminas of very low solubility with primary isometric particles of 10 or 40 nm, and synthetic iron oxide black (Fe3O4 pigment grade). Three metrics of dose (actual mass concentration, surface area concentration, mass-based Lung Burden) were compared with pulmonary toxicity characterized by bronchoalveolar lavage. The results of this analysis provide strong evidence that pulmonary toxicity (inflammation) corresponds best with the mass-based cumulative Lung exposure dose. The inhalation study with a MMAD of ≈0.5 μm yielded a higher pulmonary dose than MMADs in the range of 1–2 μm, a range most commonly used in repeated exposure inhalation studies. Hence, a key premise for the dosimetric adjustment across species is that comparable Lung tissue doses should cause comparable effects. From that perspective, the determination of mass-based pulmonary Lung Burdens appears to be amongst the most important and critical nominator of dose and dose-related pulmonary toxicity.

  • pulmonary toxicity and fate of agglomerated 10 and 40 nm aluminum oxyhydroxides following 4 week inhalation exposure of rats toxic effects are determined by agglomerated not primary particle size
    Toxicological Sciences, 2009
    Co-Authors: Jurgen Pauluhn
    Abstract:

    Inhaled polydisperse micronsized agglomerated particulates composed of nanosized primary particles may exert their pulmonary toxicity in either form, depending on whether these tightly associated structures are disintegrated within the biological system or not. This hypothesis was tested in a rat bioassay using two calcined aluminum oxyhydroxides (AlOOH) consisting of primary particles in the range of 10-40 nm. Male Wistar rats were nose-only exposed to 0.4, 3, and 28 mg/m(3) in two 4-week (6 h/day, 5 days/week) inhalation studies followed by a 3-month postexposure period. The respective mass median aerodynamic diameter (MMAD) of agglomerated particles in inhalation chambers was 1.7 and 0.6 mum. At serial sacrifices, pulmonary toxicity was characterized by bronchoalveolar lavage (BAL) and histopathology. The retention kinetics of aluminum (Al) was determined in Lung tissue, BAL cells, and selected extrapulmonary organs, including Lung-associated lymph nodes (LALNs). Significant changes in BAL, Lung, and LALN weights occurred at 28 mg/m(3). Histopathology revealed alveolar macrophages with enlarged and foamy appearance, increased epithelial cells, inflammatory cells, and focal septal thickening. The determination of aluminum in Lung tissue shows that the cumulative Lung dose was higher following exposure to AlOOH-40 nm/MMAD-0.6 mum than to AlOOH-10 nm/MMAD-1.7 mum, despite identical exposure concentrations. The associated pulmonary inflammatory response appears to be principally dependent on the agglomerated rather than primary particle size. Despite high Lung Burdens, conclusively increased extrapulmonary organ Burdens did not occur at any exposure concentration and postexposure time point. Particle-induced pulmonary inflammation was restricted to cumulative doses exceeding approximately 1 mg AlOOH/g Lung following 4-week exposure at 28 mg/m(3). It is concluded that the pulmonary toxicity of nanosized, agglomerated AlOOH particles appears to be determined by the size of agglomerated rather than primary particles, whereas the clearance half-time of particles appears to increase with decreased primary particle size. However, in regard to toxicokinetics, this outcome is highly contingent upon the total Lung Burden and especially whether overloading or non-overloading conditions were attained or not. In order to reliably demonstrate retention-related different characteristics in toxicity and fate of poorly soluble (nano)particles postexposure periods of at least 3 months appear to be indispensible.

  • pulmonary toxicity and fate of agglomerated 10 and 40 nm aluminum oxyhydroxides following 4 week inhalation exposure of rats toxic effects are determined by agglomerated not primary particle size
    Toxicological Sciences, 2009
    Co-Authors: Jurgen Pauluhn
    Abstract:

    Inhaled polydisperse micronsized agglomerated particulates composed of nanosized primary particles may exert their pulmonary toxicity in either form, depending on whether these tightly associated structures are disintegrated within the biological system or not. This hypothesis was tested in a rat bioassay using two calcined aluminum oxyhydroxides (AlOOH) consisting of primary particles in the range of 10–40 nm. Male Wistar rats were nose-only exposed to 0.4, 3, and 28 mg/m 3 in two 4-week (6 h/day, 5 days/week) inhalation studies followed by a 3-month postexposure period. The respective mass median aerodynamic diameter (MMAD) of agglomerated particles in inhalation chambers was 1.7 and 0.6 mm. At serial sacrifices, pulmonary toxicity was characterized by bronchoalveolar lavage (BAL) and histopathology. The retention kinetics of aluminum (Al) was determined in Lung tissue, BAL cells, and selected extrapulmonary organs, including Lung-associated lymph nodes (LALNs). Significant changes in BAL, Lung, and LALN weights occurred at 28 mg/ m 3 . Histopathology revealed alveolar macrophages with enlarged and foamy appearance, increased epithelial cells, inflammatory cells, and focal septal thickening. The determination of aluminum in Lung tissue shows that the cumulative Lung dose was higher following exposure to AlOOH-40 nm/MMAD-0.6 mm than to AlOOH-10 nm/MMAD-1.7 mm, despite identical exposure concentrations. The associated pulmonary inflammatory response appears to be principally dependent on the agglomerated rather than primary particle size. Despite high Lung Burdens, conclusively increased extrapulmonary organ Burdens did not occur at any exposure concentration and postexposure time point. Particleinduced pulmonary inflammation was restricted to cumulative doses exceeding approximately 1 mg AlOOH/g Lung following 4week exposure at 28 mg/m 3 . It is concluded that the pulmonary toxicity of nanosized, agglomerated AlOOH particles appears to be determined by the size of agglomerated rather than primary particles, whereas the clearance half-time of particles appears to increase with decreased primary particle size. However, in regard to toxicokinetics, this outcome is highly contingent upon the total Lung Burden and especially whether overloading or nonoverloading conditions were attained or not. In order to reliably

Charles F Redinger - One of the best experts on this subject based on the ideXlab platform.

Richard A Lemen - One of the best experts on this subject based on the ideXlab platform.

  • occupational exposure to chrysotile asbestos and cancer risk a review of the amphibole hypothesis
    American Journal of Public Health, 1996
    Co-Authors: Leslie T Stayner, David A. Dankovic, Richard A Lemen
    Abstract:

    OBJECTIVES. This article examines the credibility and policy implications of the "amphibole hypothesis," which postulates that (1) the mesotheliomas observed among workers exposed to chrysotile asbestos may be explained by confounding exposures to amphiboles, and (2) chrysotile may have lower carcinogenic potency than amphiboles. METHODS. A critical review was conducted of the Lung Burden, epidemiologic, toxicologic, and mechanistic studies that provide the basis for the amphibole hypothesis. RESULTS. Mechanistic and Lung Burden studies do not provide convincing evidence for the amphibole hypothesis. Toxicologic and epidemiologic studies provide strong evidence that chrysotile is associated with an increased risk of Lung cancer and mesothelioma. Chrysotile may be less potent than some amphiboles for inducing mesotheliomas, but there is little evidence to indicate lower Lung cancer risk. CONCLUSIONS. Given the evidence of a significant Lung cancer risk, the lack of conclusive evidence for the amphibole hyp...

  • occupational exposure to chrysotile asbestos and cancer risk a review of the amphibole hypothesis
    American Journal of Public Health, 1996
    Co-Authors: Leslie T Stayner, David A. Dankovic, Richard A Lemen
    Abstract:

    OBJECTIVES. This article examines the credibility and policy implications of the "amphibole hypothesis," which postulates that (1) the mesotheliomas observed among workers exposed to chrysotile asbestos may be explained by confounding exposures to amphiboles, and (2) chrysotile may have lower carcinogenic potency than amphiboles. METHODS. A critical review was conducted of the Lung Burden, epidemiologic, toxicologic, and mechanistic studies that provide the basis for the amphibole hypothesis. RESULTS. Mechanistic and Lung Burden studies do not provide convincing evidence for the amphibole hypothesis. Toxicologic and epidemiologic studies provide strong evidence that chrysotile is associated with an increased risk of Lung cancer and mesothelioma. Chrysotile may be less potent than some amphiboles for inducing mesotheliomas, but there is little evidence to indicate lower Lung cancer risk. CONCLUSIONS. Given the evidence of a significant Lung cancer risk, the lack of conclusive evidence for the amphibole hyp...

James O Rasmuson - One of the best experts on this subject based on the ideXlab platform.

Vincent Castranova - One of the best experts on this subject based on the ideXlab platform.

  • inhalation exposure to carbon nanotubes cnt and carbon nanofibers cnf methodology and dosimetry
    Journal of Toxicology and Environmental Health-part B-critical Reviews, 2015
    Co-Authors: Gunter Oberdorster, Vincent Castranova, Bahman Asgharian, Phil Sayre
    Abstract:

    Carbon nanotubes (CNT) and nanofibers (CNF) are used increasingly in a broad array of commercial products. Given current understandings, the most significant life-cycle exposures to CNT/CNF occur from inhalation when they become airborne at different stages of their life cycle, including workplace, use, and disposal. Increasing awareness of the importance of physicochemical properties as determinants of toxicity of CNT/CNF and existing difficulties in interpreting results of mostly acute rodent inhalation studies to date necessitate a reexamination of standardized inhalation testing guidelines. The current literature on pulmonary exposure to CNT/CNF and associated effects is summarized; recommendations and conclusions are provided that address test guideline modifications for rodent inhalation studies that will improve dosimetric extrapolation modeling for hazard and risk characterization based on the analysis of exposure-dose-response relationships. Several physicochemical parameters for CNT/CNF, including shape, state of agglomeration/aggregation, surface properties, impurities, and density, influence toxicity. This requires an evaluation of the correlation between structure and pulmonary responses. Inhalation, using whole-body exposures of rodents, is recommended for acute to chronic pulmonary exposure studies. Dry powder generator methods for producing CNT/CNF aerosols are preferred, and specific instrumentation to measure mass, particle size and number distribution, and morphology in the exposure chambers are identified. Methods are discussed for establishing experimental exposure concentrations that correlate with realistic human exposures, such that unrealistically high experimental concentrations need to be identified that induce effects under mechanisms that are not relevant for workplace exposures. Recommendations for anchoring data to results seen for positive and negative benchmark materials are included, as well as periods for postexposure observation. A minimum data set of specific bronchoalveolar lavage parameters is recommended. Retained Lung Burden data need to be gathered such that exposure-dose-response correlations may be analyzed and potency comparisons between materials and mammalian species are obtained considering dose metric parameters for interpretation of results. Finally, a list of research needs is presented to fill data gaps for further improving design, analysis, and interpretation and extrapolation of results of rodent inhalation studies to refine meaningful risk assessments for humans.

  • pulmonary fibrotic response to aspiration of multi walled carbon nanotubes
    Particle and Fibre Toxicology, 2011
    Co-Authors: Robert R Mercer, Ann F Hubbs, James F Scabilloni, Liying Wang, Lori A Battelli, Sherri Friend, Vincent Castranova, Dale W Porter
    Abstract:

    Background Multi-walled carbon nanotubes (MWCNTs) are new manufactured nanomaterials with a wide spectrum of commercial applications. To address the hypothesis that MWCNTs cause persistent pulmonary pathology, C57BL/6J mice were exposed by pharyngeal aspiration to 10, 20, 40 or 80 μg of MWCNTs (mean dimensions of 3.9 μm × 49 nm) or vehicle. Lungs were preserved at 1, 7, 28 and 56 days post- exposure to determine the potential regions and target cells for impact by MWCNT Lung Burden. Morphometric measurement of Sirius Red staining was used to assess the connective tissue response.

  • pulmonary response to intratracheal instillation of ultrafine versus fine titanium dioxide role of particle surface area
    Particle and Fibre Toxicology, 2008
    Co-Authors: Choudari Kommineni, Tina M Sager, Vincent Castranova
    Abstract:

    Background: The production and use of nanoparticles is growing rapidly due to the unique physical and chemical properties associated with their nano size and large surface area. Since nanoparticles have unique physicochemical properties, their bioactivity upon exposure to workers or consumers is of interest. In this study, the issue of what dose metric (mass dose versus surface area dose) is appropriate for toxicological studies has been addressed. Rats were exposed by intratracheal instillation to various doses of ultrafine or fine TiO2 . At 1, 7, or 42 days postexposure, inflammatory and cytotoxic potential of each particle type was compared on both a mass dosage (mg/rat) as well as an equal surface area dosage (cm2 of particles per cm2 of alveolar epithelium) basis. Results: The findings of the study show that on a mass basis the ultrafine particles caused significantly more inflammation and were significantly more cytotoxic than the fine sized particles. However, when doses were equalized based on surface area of particles delivered, the ultrafine particles were only slightly more inflammogenic and cytotoxic when compared to the fine sized particles. Lung Burden data indicate that ultrafine TiO2 appears to migrate to the interstitium to a much greater extent than fine TiO 2 . Conclusion: This study suggests that surface area of particles may be a more appropriate dose metric for pulmonary toxicity studies than mass of particles.

  • effect of inhaled crystalline silica in a rat model time course of pulmonary reactions
    Molecular and Cellular Biochemistry, 2002
    Co-Authors: Vincent Castranova, Ann F Hubbs, Dale W Porter, Lyndell Millecchia, Jane Y C, Alexander W Teass
    Abstract:

    Numerous investigations have been conducted to elucidate mechanisms involved in the initiation and progression of silicosis. However, most of these studies involved bolus exposure of rats to silica, i.e. intratracheal instillation or a short duration inhalation exposure to a high dose of silica. Therefore, the question of pulmonary overload has been an issue in these studies. The objective of the current investigation was to monitor the time course of pulmonary reactions of rats exposed by inhalation to a non-overload level of crystalline silica. To accomplish this, rats were exposed to 15 mg/m3 silica, 6 h/day, 5 days/week for up to 116 days of exposure. At various times (5–116 days exposure), animals were sacrificed and silica Lung Burden, Lung damage, inflammation, NF-κB activation, reactive oxygen species and nitric oxide production, cytokine production, alveolar type II epithelial cell activity, and fibrosis were monitored. Activation of NF-κB/DNA binding in BAL cells was evident after 5 days of silica inhalation and increased linearly with continued exposure. Parameters of pulmonary damage, inflammation and alveolar type II epithelial cell activity rapidly increased to a significantly elevated but stable new level through the first 41 days of exposure and increased at a steep rate thereafter. Pulmonary fibrosis was measurable only after this explosive rise in Lung damage and inflammation, as was the steep increase in TNF-α and IL-1 production from BAL cells and the dramatic rise in lavageable alveolar macrophages. Indicators of oxidant stress and pulmonary production of nitric oxide exhibited a time course which was similar to that for Lung damage and inflammation with the steep rise correlating with initiation of pulmonary fibrosis. Staining for iNOS and nitrotyrosine was localized in granulomatous regions of the Lung and bronchial associated lymphoid tissue. Therefore, these data demonstrate that the generation of oxidants and nitric oxide, in particular, is temporally and anatomically associated with the development of Lung damage, inflammation, granulomas and fibrosis. This suggests an important role for nitric oxide in the initiation of silicosis.

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