Higher Lung Burdens Research Articles

Asbestos Lung Burden Does Not Predict Survival in Malignant Pleural Mesothelioma: A Necropsy-Based Study of 185 Cases

IntroductionMalignant pleural mesothelioma is an asbestos-related disease with poor survival. The prognostic role of histologic subtype is well established. Some studies (without a biological hypothesis) suggested that higher asbestos lung burden is associated with reduced survival. MethodsWe selected subjects from two series of necropsies: residents in Brescia province (North-West Italy) and workers (or persons living with them) employed in the Monfalcone shipyards (North-East Italy). Asbestos fibers and asbestos bodies in lung samples were counted using a scanning electron and an optical microscope, respectively. Separately in the two series, we analyzed median survival time and fitted multivariable Cox regression models (adjusted for sex, period and age at diagnosis, and histopatholocical diagnosis) to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for three levels of asbestos fiber counts (reference: <1 million fibers/g of dry lung tissue). ResultsWe analyzed 185 necropsies, 83 in Brescia and 102 in Monfalcone. Despite a much higher lung burden in Monfalcone patients, median survival was slightly shorter in Brescia (8.3 mo) than in Monfalcone (10.2 mo). In Brescia, medium (1.0–9.9) and high (10+) fiber burden HRs were 0.91 (95% CI: 0.54–1.53) and 1.23 (95% CI: 0.41–3.70), respectively. In Monfalcone, the corresponding HRs were 1.18 (95% CI: 0.59–2.35) and 1.63 (95% CI: 0.77–3.45), respectively. ConclusionsNo relationship between asbestos lung burden and survival was found. Histologic subtype was the strongest prognostic determinant.

Lung deposition patterns of MWCNT vary with degree of carboxylation

Functionalization of multi-walled carbon nanotubes (MWCNT) is known to affect the biological response (e.g. toxicity, inflammation) in vitro and in vivo. However, the reasons for these changes in vivo are not well described. This study examined the degree of MWCNT functionalization with regard to in vivo mouse lung distribution, particle retention, and resulting pathology. A commercially available MWCNT (source MWCNT) was functionalized (f-MWCNT) by systematically varying the degree of carboxylation on the particle’s surface. Following a pilot study using seven variants, two f-MWCNT variants were chosen and for lung pathology and particle distribution using oropharyngeal aspiration administration of MWCNT in Balb/c mice. Particle distribution in the lung was examined at 7 and 28 days post-instillation by bright-field microscopy, CytoViva hyperspectral dark-field imaging, and Stimulated Raman Scattering (SRS) microscopy. Examination of the lung tissue by bright-field microscopy showed some acute inflammation for all MWCNT that was highest with source MWCNT. Hyperspectral imaging and SRS were employed to assess the changes in particle deposition and retention. Highly functionalized MWCNT had a higher lung burden and were more disperse. They also appeared to be associated more with epithelial cells compared to the source and less functionalized MWCNT that were mostly interacting with alveolar macrophages (AM). These results showing a slightly reduced pathology despite the extended deposition have implications for the engineering of safer MWCNT and may establish a practical use as a targeted delivery system.

Surface area is the biologically most effective dose metric for acute nanoparticle toxicity in the lung

In this study we provide guidance on the biologically most relevant dose metric for pulmonary toxicity of biopersistent, spherical nanoparticles (NPs). A retrospective analysis of nine in vivo studies on particle-induced, acute pulmonary toxicity in animal models (mouse, rat) was performed encompassing five different types of nanomaterials (polystyrene, titanium dioxide, carbonaceous materials, transition metal oxides (Co, Ni, Zn) and hydrothermally synthesized α-quartz) with a wide range of primary particle diameters (9–535nm) and mass-specific BET surface areas (6–800m2/g). The acute influx of polymorphonuclear neutrophils (PMNs) into the lungs after intratracheal instillation of NPs was chosen as a toxicological endpoint for acute lung inflammation. The allometrically scaled toxicological data were investigated with respect to various dose metrics, namely (primary) particle number, joint length, BET and geometric surface area, volume and mass.Surface area is identified as the biologically most relevant dose metric for spherical NPs explaining about 80% of the observed variability in acute pulmonary toxicity (R2=0.77). None of the other dose metrics explains more than 50% of the observed variability in pulmonary inflammation. Moreover, using surface area as the dose metric allows identification of material-based toxicity classes independent of particle size. Typical materials without intrinsic toxicity – here referred to as low-solubility, low-toxicity (LSLT) materials – show low surface-specific toxicity with an EC50 dose of 175m2/g-lung (geometric mean; σg=2.2), where EC50 represents the dose inducing 50% of the maximum effect (here 30% PMN). In contrast, transition metal oxides (here Co, Ni, Zn) – materials known for their intrinsic toxicity – display a 12-fold enhanced surface-specific toxicity compared to LSLT particles (EC50=15m2/g-lung).This analysis implies that surface-related modes of action are driving acute pulmonary toxicity for the types of NPs investigated here. The relevance of other dose metrics such as number and volume is acknowledged in the context of different modes of action, namely shape-induced toxicity (fiber paradigm) and extremely high particle lung burden (overload conditions), respectively. So which dose metric should be monitored by aerosol scientists involved in health related aerosol exposure measurements? The short answer is – all of them (except length), but there is a strong preference towards surface area.

Influence of agglomeration and specific lung lining lipid/protein interaction on short-term inhalation toxicity

Lung lining fluid is the first biological barrier nanoparticles (NPs) encounter during inhalation. As previous inhalation studies revealed considerable differences between surface functionalized NPs with respect to deposition and toxicity, our aim was to investigate the influence of lipid and/or protein binding on these processes. Thus, we analyzed a set of surface functionalized NPs including different SiO2 and ZrO2 in pure phospholipids, CuroSurfTM and purified native porcine pulmonary surfactant (nS). Lipid binding was surprisingly low for pure phospholipids and only few NPs attracted a minimal lipid corona. Additional presence of hydrophobic surfactant protein (SP) B in CuroSurfTM promoted lipid binding to NPs functionalized with Amino or PEG residues. The presence of the hydrophilic SP A in nS facilitated lipid binding to all NPs. In line with this the degree of lipid and protein affinities for different surface functionalized SiO2 NPs in nS followed the same order (SiO2 Phosphate ∼ unmodified SiO2 < SiO2 PEG < SiO2 Amino NPs). Agglomeration and biomolecule interaction of NPs in nS was mainly influenced by surface charge and hydrophobicity. Toxicological differences as observed in short-term inhalation studies (STIS) were mainly influenced by the core composition and/or surface reactivity of NPs. However, agglomeration in lipid media and lipid/protein affinity appeared to play a modulatory role on short-term inhalation toxicity. For instance, lipophilic NPs like ZrO2, which are interacting with nS to a higher extent, exhibited a far higher lung burden than their hydrophilic counterparts, which deserves further attention to predict or model effects of respirable NPs.

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

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.

TOXICOKINETICS AND EFFECTS OF FIBROUS AND NONFIBROUS PARTICLES

Chronic inhalation of fibrous and nonfibrous particles by rats at high concentrations results in lung tumor formation if the particles are poorly soluble in the lung. Even rather benign nonfibrous particles such as TiO 2 produce this result. One significant change during a chronic inhalation exposure of poorly soluble particles of low cytotoxicity (PSP) is an impairment of normal clearance mechanisms in the alveolar region of the lung in rats, resulting in a continued buildup to high lung burdens accompanied by chronic alveolar inflammation, fibrosis, and mutational events. Since these are obviously high-dose effects, questions about their extrapolation to humans exposed to much lower concentrations have been raised. Results of key studies reported for chronic inhalation of PSP in rats indicate that mechanisms of PSP-induced lung tumors at high doses do not operate at low dose levels. Furthermore, the existence of two thresholds can be postulated: One is a dosimetric threshold for the endpoint alveolar macrophage-mediated clearance, which is related to lung particle overload. The other is a mechanistic threshold for the endpoint mutation, which is determined by the level of antioxidant defenses to counter-balance reactive oxidant species released by activated inflammatory cells. A no-observed-adverse-effect level (NOAEL) could therefore be based on avoiding alteration of the toxicokinetic of the particles such that the lung burdens stay below the dosimetric threshold. The suggestion that PSP-associated organic compounds (e.g., diesel particulate matter) contribute to the lung tumor responses in rats observed in chronic inhalation studies is not supported by experimental data from in vivo studies. It can be concluded that high-dose rat lung tumors due to PSP should not be used for low-dose extrapolations, and no significant contribution to human lung cancer risk can be predicted from levels of PSP below lung overload. With respect to the pulmonary toxicokinetics of inhaled fibrous particles, the biopersistence of long fibers (>20 µm) which cannot be phagocytized by alveolar macrophages is a key parameter related to long-term carcinogenic effects. Long fibers with a very low biopersistence should not be considered as carcinogenic. Since the clearance kinetics of fibers can generally be described by a biphasic or multiphasic pattern - fast initial and slow final phase - it is essential that the slow phase of the retention kinetics of fibers longer than 20 µm is considered in a biopersistence assay. Based on the results of such assay, fibers can be classified into one of two categories: a biopersistent fiber that cannot be dissolved in the lung within an acceptable time period; or a biosoluble fiber when even long nonphagocytizable fibers will be disappearing rapidly from the lung. However, in addition to biopersistence, it should be mandatory to evaluate fiber toxicity in an appropriate assay relative to a fiber whose long-term effects are well known. Moreover, for organic fibers it is likely that different rules may have to be established for characterization of their toxic and carcinogenic potential.

THE RELEVANCE OF THE RAT LUNG RESPONSE TO PARTICLE OVERLOAD FOR HUMAN RISK ASSESSMENT: A Workshop Consensus Report

On 23-24 March 1998, the International Life Sciences Institute (ILSI) Risk Science Institute convened a workshop entitled ''Relevance of the Rat Lung Response to Particle Overload for Human Risk Assessment. The workshop addressed the numerous study reports of lung tumors in rats resulting from chronic inhalation exposures to poorly soluble, nonfibrous particles of low acute toxicity and not directly genotoxic. These poorly soluble particles, indicated by the acronym PSPs (e.g., carbon black, coal dust, diesel soot, nonasbestiform talc, and titanium dioxide), elicit tumors in rats when deposition overwhelms the clearance mechanisms of the lung resulting in a condition referred to as ''overload. These PSPs have been shown not to induce tumors in mice and hamsters, and the available data in humans are consistently negative. The objectives were twofold: (1) to provide guidance for risk assessment on the interpretation of neoplastic and nonneoplastic responses of the rat lung to PSPs; and (2) to identify important data gaps in our understanding of the lung responses of rats and other species to PSPs. Utilizing the five critical reviews of relevant literature that follow herein and the combined expertise and experience of the 30 workshop participants, a number of questions were addressed. The consensus views of the workshop participants are presented in this report. Because it is still not known with certainty whether high lung burdens of PSPs

Evaluation of workers exposed to dust containing hard metals and aluminum oxide.

Fourteen worker exposed to hard metals and aluminum oxide were evaluated. Six heavily exposed workers underwent bronchoscopy and bronchoalveolar lavage, and five workers underwent transbronchial biopsy. Microchemical analysis of transbronchial biopsies showed a high lung burden of exogenous particles, especially metal related to their hard metals exposure. Lung tissue and cellular changes, which were associated with exposure to hard metal and aluminum oxide, corresponded well with the microanalytic test results. Three workers had at biopsy diffuse interstitial inflammatory changes: two of them were asymptomatic with normal chest X-ray films, and one had clinically evident disease with severe giant cell inflammation. Two other workers showed focal inflammation. The worker showing clinical disease and one asymptomatic worker with interstitial inflammatory changes had evaluated bronchoalveolar lavage fluid-eosinophilia counts. These two were father (with clinical disease) and son (asymptomatic).

EXTRAPOLATION MODELING OF PARTICLE DEPOSITION AND RETENTION FROM RATS TO HUMANS

Rodents have often been used as surrogates for humans to study biological responses from exposure to airborne particles. To interpret experimental data of rodent studies and to extrapolate results to potential human exposures, interspecies comparisons of particle dosimetry in the lung are necessary. This article deals with dosimetry studies in humans and rats by mathematical models using diesel exhaust particles as an example exposure material, the diesel particle was modeled as a submicrometer-sized particle consisting of a carbonaceous core and associated organics. The dosimetry results showed that total and alveolar deposition fractions in a breathing cycle in humans and rats were similar, but there were large differences between the two species in deposition rate and in particle retention per gram of lung. A new formula was also derived from existing experimental data for the alveolar clearance rate in rats at high lung burdens. This formula was extrapolated to humans based upon a hypothesis previousl...

The NTP Talc Inhalation Study: A Critical Appraisal Focused on Lung Particle Overload

Recently published results in a NTP report of a 2-year inhalation study with talc in rats and mice seem to fit the category of being associated with particle overload quite well: Exposure concentrations of 6 and 18 mg/m 3 induced pulmonary inflammation and fibrosis in male and female rats and induction of lung tumors (in female rats only) of the high exposure group; mice of either sex showed an inflammatory response but did not show pulmonary fibrosis or lung tumors. Analysis of the particle accumulation kinetics in lungs of both rats and mice indeed shows that lung overload had been reached at both exposure concentrations in both species resulting in increased talc accumulation of high lung burdens, This and the chronic inflammatory response-indicate that the maximum tolerated dose (MTD) had been exceeded at both exposure levels. This result was predictable based on the outcome of a 4-week range-finding study prior to initiation of the chronic talc study; however, the short duration of the range-finding study may have been inadequate to give great confidence in the prediction and,therefore may have accounted for the failure to include a concentration below the MTD in the chronic study. Further analysis of the results of the chronic talc study show that talc particles behave like other low-toxicity particles such as TiO 2 and toner with respect to effects on lung clearance and chronic pulmonary inflammation, The conclusion of the NTP report that there is clear evidence of pulmonary carcinogenicity of talc in female rats should, therefore, be qualified by a statement that this is a secondary effect due to the high pulmonary particle load and its associated chronic toxicity. Accordingly, the relevancy of the tumors observed in the female high-exposure group for occupational human exposures may be questionable.

Lung Particle Overload: Implications for Occupational Exposures to Particles

Chronic pulmonary inflammation, pulmonary fibrosis, and even lung tumors developed in a number of chronic inhalation studies in rats with highly insoluble nonfibrous particles of low cytotoxicity. Concerns were expressed that these responses are due to excessive particulate lung burdens, and the term "particle overload" was coined to characterize these conditions. The hallmark of the particle-overloaded lung is an impairment of alveolar macrophage (AM)-mediated lung clearance which has been demonstrated in all species tested so far and which eventually leads to accumulation of excessive lung burdens. Experimental evidence suggests that the volume of the particles phagocytized by AM: is most critical for causing their impaired clearance function, and that the condition of lung overload is reached once the retained lung particle burden reaches a level equivalent to a volume of approximately 1 μl/g of lung. Cytotoxic particles also cause impaired AM clearance function, yet at a much lower lung burden which does not qualify as particle overload. Significant species differences exist with respect to the induction of adverse chronic effects in response to lung overload; i.e., mice and hamsters are less prone to developing chronic inflammation and pulmonary fibrosis, and lung tumors have been observed only in rat studies. Lung tumors or fibrosis in the rats were seen only at lung burdens having caused impaired particle clearance, and a threshold dose for the adverse chronic effects can be postulated which is defined by a lung particle burden not causing impairment of clearance. Thus, the lung tumors observed in chronic rat studies at very high particulate exposure concentrations may not be relevant for human extrapolation to low-exposure concentrations. Evidence in humans suggests that particle-overloaded lungs, e.g., in coal workers, respond with fibrosis, but no increased incidence of lung tumors has been found in this group. However, it cannot be excluded that other types of chronically inhaled particles may have a carcinogenic potential in the human lung if accumulating to very high lung burdens. More research is needed for a detailed understanding of the basic mechanism leading to nonfibrous particle-induced tumorigenesis in the lungs of different species. Altered particle accumulation and retention kinetics and chronic inflammation in the overloaded lung indicate that the maximum tolerated dose (MTD) has been exceeded. No specific guidelines for inhalation studies defining the MTD have been established; general guidelines are not necessarily applicable for chronic inhalation studies. One suggestion is to define the MTD in chronic particle inhalation studies as a maximum functionally tolerated dose (MFTD) based on a functional parameter of lung particle clearance. However, other endpoints based on an evaluation of alveolar inflammation and lung histology should be included as well. For the estimation of the MTD or MFTD a range-finding study of sufficient length, preferably 3 months, would be required. It is important to realize, however, that with increasing chronicity of exposure and increasing age of the animals, a shift in the dose-response relationship may occur. One important conclusion from our understanding of lung particle overload is that occupational exposure limits should be set to prevent impaired AM-mediated lung clearance which will-avert the accumulation of high pulmonary dust burdens; conceivably, this will also prevent the subsequent induction of adverse chronic effects including inflammation, fibrosis, and tumors since these particle-induced tumors are likely secondary to continued inflammation, tissue damage, and cell proliferation. Extrapolation from rat studies of such exposure limits predicts that present occupational standards for highly insoluble particles of low cytotoxicity may not prevent lung overload in humans and should be reevaluated.

Low frequency of alterations in p53, K-ras, and mdm2 in rat lung neoplasms induced by diesel exhaust or carbon black.

Inhalation of diesel exhaust (DE), which contains soot particles with adsorbed mutagenic organic compounds, and its virtually mutagen-free soot particle analog, carbon black (CB), produce similar types and prevalences of pulmonary neoplasms in chronically exposed F344 rats. This result suggests that DE-induced neoplasia develops from the effects of a high lung burden of carbonaceous particles rather than from the genotoxicity of organic constituents. In this investigation, pulmonary carcinomas from rats exposed to DE or CB were analyzed for alterations in K-ras and p53 to determine if mutations caused by these agents are also similar. K-ras and p53 were chosen for this study because mutation patterns of these genes in lung neoplasms have been associated with specific exposures. A low frequency (3/50) and variable pattern of activating mutations were identified in codons 12 and 61 of the K-ras gene. Immunoreactive levels of p53 protein, suggesting gene dysfunction, were present in 7/13 squamous cell or adenosquamous carcinomas, regardless of the associated exposure. However, single-strand conformational polymorphism analysis and direct sequencing of p53 did not detect any mutations in these neoplasms. No immunoreactivity or mutations in p53 were observed in adenocarcinomas. The increased level of p53 protein in the squamous carcinomas is not explained by stabilization by the mdm2 gene product, because this protein was not overexpressed based on immunohistochemical analysis. No pattern of mutation was detected that would suggest a differential mechanism of carcinogenicity between DE and CB; however, inactivation of the p53 pathway may have a role in the development of rat lung neoplasms with a squamous cell carcinoma component.

MESOTHELIOMAS AND CHRYSOTILE

Mesotheliomas are rare. While most are reported to be associated with exposure to durable fibres, a proportion are not caused by the inhalation of fibres at all. Reports of individual cases and studies of small groups are unreliable as evidence of cause because: (a) diagnosis is often unreliable; (b) even if chrysotile fibres are found in lung tissues, the mesothelioma may still be spontaneous. Present knowledge has not progressed much since 1964 when the absence of cases of mesothelioma in amosite and chrysotile miners in South Africa and the very low incidence in Canadian mines was known but not believed. Now we know this information was correct. The significance of low-level amphibole exposures in predominantly chrysotile mixes was not appreciated until studies of fibres in lungs using electron microscopy showed the high lung burden of amphibole fibres in the 1970s and 1980s. The effect of these findings is to make most European and U.S.A. factory cohorts inappropriate for the evaluation of chrysotile mesothelioma risk. Reviewing the current evidence published and unpublished, it seems likely that chrysotile uncontaminated by tremolite may not have caused any mesotheliomas even at high cumulative life-time exposures. Information on the mesothelioma risk among chrysotile user populations using fibres not containing tremolite is badly needed.

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat. Newton, P. E., Bolte, H. F., Daly, I. W., Pillsbury, B. D., Terrill, J. B., Drew, R. T., Ben-Dyke, R., Sheldon, A. W., and Rubin, L. F. (1994). Fundam. Appl. Toxicol. 22, 561-576.Fischer 344 rats were exposed by inhalation to Sb2O3 (antimony trioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and 23.46 mg/m3 for 6 hr/day, 5 days/week for 13 weeks followed by a 27-week observation period. Subsequently, an inhalation oncogenicity study was conducted at exposure levels of 0, 0.06, 0.51, and 4.50 mg/m3 for 12 months followed by a 12-month observation period. The Sb2O3 in the subchronic study had a mass median aerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean ± SD) with a geometric standard deviation (GSD) of 1.57 ± 0.06. In the chronic study, the MMAD was 3.76 ± 0.84 and the GSD was 1.79 ± 0.32. Except for the eyes, no adverse clinical observations were attributed to Sb2O3 in either study. In the subchronic study, corneal irregularities were seen after about 2 weeks of exposure and did not abate during the observation period. In the chronic study, ophthalmoscopic evaluation at 24 months revealed a dose-related increase in cataracts of 11, 24, 28, and 32% (both sexes combined) for each group, respectively. Body weights were significantly lower (6%) than the control group's weights in the 23.46 mg/m3 males in the subchronic study. These rats did not recover this weight during the 27-week observation period. Body weights of the females in both studies and males in the chronic study were unaffected. There were no Sb2O3 effects on clinical chemistry or hematology in either study. Mean absolute and relative lung weights were significantly increased in the 4.92 and 23.46 mg/m3 groups in the subchronic study. The 23.46 mg/m3 group's lung weights did not recover to control levels during the 27-week observation period. Lung weights for rats in the chronic study were unaffected. Microscopic changes in the lungs in the subchronic and chronic study were limited to subacute-chronic interstitial inflammation, increased numbers of alveolar-intraalveolar macrophages, foreign material in the alveolar-intraalveolar macrophages in the peribronchial and perivascular (chronic study only) lymphoid aggregates and in the peribronchial lymph nodes, granulomatous inflammation/granulomas, and fibrosis. In the chronic study, any observed neoplasms occurred with comparable incidence among all groups and were within the historical range for controls. Clearance of Sb2O3 from the lung was burden dependent and was reduced by 80% in the 4.50 mg/m3 group in the chronic study. The previously reported studies, which found Sb2O3 to be a carcinogen, were run at higher lung burdens. Under the exposure conditions of the current study, Sb2O3 was not a carcinogen.

Retention Modeling of Diesel Exhaust Particles in Rats and Humans

The objective of this study was to predict the lung burden in rats and humans of diesel exhaust particles from automobile emissions by means of a mathematical model. We previously developed a model to predict the deposition of diesel exhaust particles in the lungs of these species. In this study, the clearance and retention of diesel exhaust particles deposited in the lung are examined. A diesel particle is composed of a carbonaceous core (soot) and adsorbed organics. These materials can be removed from the lung after deposition by two mechanisms: (1) mechanical clearance, provided by mucociliary transport in the ciliated airways as well as macrophage phagocytosis and migration in the nonciliated airways, and (2) clearance by dissolution. To study the clearance of diesel exhaust particles from the lung, we used a compartmental model consisting of four anatomical compartments: nasopharyngeal, tracheobronchial, alveolar, and the lung-associated lymph node compartments. We also assumed a particle model made up of material components according to the characteristics of clearance: (1) a carbonaceous core of about 80 percent of particle mass, (2) slowly cleared organics of about 10 percent of particle mass, and (3) fast-cleared organics accounting for the remaining 10 percent of particle mass. The kinetic equations of the retention model were first developed for Fischer-344 rats. The transport rates of each material component of diesel exhaust particles (soot, slowly cleared organics, and fast-cleared organics) were derived using available experimental data and several mathematical approximations. The lung burden results calculated from the model showed that although the organics were cleared at nearly constant rates, the alveolar clearance rate of diesel soot decreased with increasing lung burden. This is consistent with existing experimental observations. At low lung burdens, the alveolar clearance rate of diesel soot was a constant, equal to the normal clearance rate controlled by macrophage migration to the mucociliary escalator, whereas at high lung burdens, the clearance rate was determined principally by transport to the lymphatic system. The retention model of diesel exhaust particles for rats was extrapolated to humans of different age groups, from birth to adulthood. To derive the transport rates for the human model, the mechanical clearance from the alveolar region of the lung was assumed to be dependent on the specific particulate burden on the alveolar surface. The reduction in the mechanical clearance in adult humans caused by exposure to high concentrations of diesel exhaust was found to be much less than that observed in rats. The reduction in children was greater than that in adults.(ABSTRACT TRUNCATED AT 400 WORDS)

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°C, resulting in either high (mean of 50 μg/kg body wt) or low (mean of 17 μg/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 γ-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°C was retained more tenaciously in the lungs (62% of the ILB retained at 180 days after exposure) than BeO calcined at 500°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°C than at 1000°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.

A kinetic model of alveolar clearance of amosite asbestos fibers from the rat lung at high lung burdens

A nonlinear compartmental model of the clearance kinetics of amosite asbestos fibers in the alveolar region of the rat lung at the dust overload condition is proposed, in which the clearance rate coefficient is dependent on the lung burden. Using this model together with a deposition model which we developed previously, we calculated the accumulation of amosite asbestos fibers in the rat lung during chronic exposure. The effects of breathing condition, exposure-concentration, and post-exposure period on the lung burden were examined in the model. Comparisons are made between the calculated lung burden and existing experimental data.

Dust Overloading of Lungs: Investigations of Various Materials, Species Differences, and Irreversibility of Effects

ABSTRACT In separate inhalation investigations, rodents (Wistar rats, Fischer-344 rats, Syrian golden hamsters, NMRI and C57BL mice) were exposed to various dusts such as test toner (polymer pigmented with carbon black), polyvinyl chloride, carbon black, diesel exhaust and two crystalline forms of titanium dioxide (anatase and rutile). The animals inhaled various concentrations (0.8 to 64 mg/m3) of these particles for up to 2 years. Alveolar clearance retardation was detectable above a retained pulmonary burden of 0.5 mg per rat lung, and a substantial decrease in the clearance rate (about a factor of 6) was observed following heavy dust loading, exceeding 10 mg dust per rat lung. Above a threshold lung burden, signs of lung overloading persisted 15 months after cessation of exposure in F-344 rats. Retardation of alveolar clearance was also observed in hamsters, commencing at higher lung burdens (normalized to lung weight) than in rats. At high dust exposure levels, persistent pulmonary inflammation was p...

Clearance, Translocation, and Excretion of Beryllium following Acute Inhalation of Beryllium Oxide by Beagle Dogs

Clearance, Translocation, and Excretion of Beryllium following Acute Inhalation of Beryllium Oxide by Beagle Dogs. FINCH, G. L., MEWHINNEY, J. A., HOOVER, M. D., EIDSON, A. R, HALEY, P. J., AND BICE, D. E. (1990). Fundam Appl. Toxicol. 15, 231–241. Beagle dogs inhaled radiolabeled beryllium oxide (7BeO) particles that were calcined at either 500 or 1000'C, resulting in either high (mean of 50 ng/kg body wt) or low (mean of 17 ug/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 -y-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'C was retained more tenaciously in the lungs (62% of the ILB retained at 180 days after exposure) than BeO calcined at 500°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*C than at 1000'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.

Alveolar Macrophages in a Particle "Overload" Condition

ABSTRACT Alveolar macrophage (AM)-mediated particle clearance from the lung via the conducting airways is an important mechanism by which relatively insoluble particles are translocated from the alveolar region. Diminution in the kinetics of removal of particles from the lung following the deposition of excessive particulate lung burdens (particle overload), which can be functionally viewed as the emergence of a sequestration compartment(s), suggests AM-related bases inasmuch as these cells are usually the primary reservoirs of deposited particles. Specific details about the mechanisms involved in AM-mediated lung clearance or about processes that may favor particle retention in the lung have not been well delineated. In the present investigation, the retention kinetics of a low to a relatively high lung burden of uniform polystyrene microspheres was examined with the highest burden studied resulting in a condition of particle overload. We also assessed the lung's free cell response to these burdens o...